OA21087A - Condensed tricyclic pyrroles as Alpha-1 Antitrypsin modulators. - Google Patents

Abstract

The disclosure provides compounds useful for treating alpha-1 antitrypsin deficiencv (AATD), according to formula (I), tautomers thereof, 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 those compounds and processes for making those compounds.

Description

CONDENSED TRICYCLIC PYRROLES AS ALPHA-1 ANTITRYPSIN

MODULATORS

This application claims the benefit of U.S. Provisional Application No. 62/847,562, filed on May 14, 2019, and U.S. Provisional Application No. 63/004,813, filed Aprîl 3, 2020, the contents of which are incorporated b y reference in their entirety.

The disclosure provides compounds that are capable of modulating alpha-1 antitypsin (A AT) activity and methods of treating alpha-1 antitrypsin deficiency (AATD) b y administering one or more such compounds.

AATD is a genetic disorder characterized by low circulating levels of AAT. While treatments for AATD exist, there îs currently no cure. AAT îs produced primarily in lîver cells and secreted into the blood, but it is also made b y other cell types including lung épithélial cells and certain white blood cells. AAT înhibits several serine proteases secreted by inflammatory cells (most notably neutrophil elastase [NE], protéinase 3, and cathepsin G) and thus protects organs such as the lung from protease-induced damage, especially during periods of inflammation.

The mutation most commonly associated with AATD involves a substitution of lysine for glutamic acid (E342K) in the SERPINA1 gene that encodes the AAT protein. This mutation, known as the Z mutation or the Z allele, leads to misfolding of the translated protein, which is therefore not secreted into the bloodstream and can polymerize within the producing cell. Consequently, circulating AAT levels in indivîduals homozygous for the Z allele (PiZZ) are markedly reduced; only approximately 15% of mutant Z-AAT protein folds correctly and is secreted by the cell. An additional conséquence of the Z mutation is that the secreted Z-AAT has reduced activity compared to wild-type protein, with 40% to 80% of normal antiprotease activity (American thoracic society/European respiratory society, Am J Respir Crit Care Med. 2003; 168(7):818-900; andOgushi et al. J Clin Invest. 1987;80(5); 1366-74.

The accumulation of polymerized Z-AAT protein within hépatocytes results in a gain-offunction cytotoxicity that can resuit in cîrrhosis or liver cancer later in life and néonatal liver disease in 12% of patients. This accumulation may spontaneously remit but can be fatal în a small number of children. The deficiency of circulating AAT results in unregulated protease activity that dégradés lung tissue over time, resulting în emphysema, a form of chronic obstructive pulmonary disease (COPD). This effect is severe in PiZZ indivîduals and typically manifests in middle âge, resulting in a décliné in quality of life and shortened lifespan (mean 68 years of âge) (Tanash et al. Int J Chron Obstruct Pulm Dis. 2016;11:1663-9). The effect îs more pronounced in PiZZ indivîduals who smoke, resulting în an even further shortened lifespan (58 years), Piitulainen and Tanash, COPD 2015; 12(1 ):36-41. PiZZ individuals account for the majority of those with clinically relevant AATD lung disease. Accordingly, there is a need for additional and effective treatments for AATD.

A mîlder form of AATD is associated with the SZ génotype in which the Z-allele îs combined with an S-allele. The S allele is associated with somewhat reduced levels of circulating AAT but causes no cytotoxicity in liver cells. The resuit is clinically significant lung disease but not liver disease. Fregonese and Stolk, Orphanet J Rare Dis. 2008; 33:16. As with the ZZ génotype, the deficiency of circulating AAT in subjects with the SZ génotype results in unregulated protease activity that dégradés lung tissue over time and can resuit in emphysema, particularly in smokers.

The current standard of care for AAT déficient individuals who hâve or show signs of developing significant lung or liver disease is augmentation therapy or protein replacement therapy. Augmentation therapy involves administration of a human AAT protein concentrate purified from pooled donor plasma to augment the missing AAT. Although infusions of the plasma protein hâve been shown to improve survival or slow the rate of emphysema progression, augmentation therapy is often not sufficient under challenging conditions such as during an active lung infection. Similarly, although protein replacement therapy shows promise in delayîng progression of disease, augmentation does not restore the normal physiological régulation of AAT in patients and efficacy has been dîfficult to demonstrate. In addition, augmentation therapy requires weekly visits for treatment and augmentation therapy cannot address liver disease, which is driven by the toxic gain-of-ftinction ofthe Z allele. Thus, there is a continuing need for new and more effective treatments for AATD.

One aspect of the invention proviâes compounds of Formulae I, I-A, I-B, I-C, I-D, 1-E, I-F, I-G, and I-H as well as tautomers of those compounds, pharmaceutically acceptable salts of those compounds and their tautomers, and deuterated dérivatives of any ofthe foregoing that can be employed in the treatment of AATD. For example, compounds of Formula 1 can be depicted as:

wherein:

(i) R is chosen from (a) CpCg linear, branched, and cyclic groups, wherein the Cj-Cg linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the C|-Cg linear, branched, and cyclic groups are optionally substituted with l-4 R^A; and (b) 5- to 14-membered aromatic rings optionally substituted with 1-4 R^A;

wherein each R^A is independently chosen from halogens, cyano, hydroxy, thiol, sulfonic acid, sulfonamide, sulfinamide, amino, amide, carboxylic acid, 5- to 10membered aromatic rings, and C_rC₆ linear, branched, and cyclic groups, wherein the amide nitrogen atom in the amide of R^A is optionally substituted with a heterocyclyl group that is optionally further substituted with oxo, wherein the Ci-Cô linear, branched, and cyclic groups are chosen from alkyl, alkoxy, thioalkyl, alkylsulfoxîde, alkylsulfonyl, alkylsulfonamide, alkylsulfinamide, aminoalkyl, and alkylamide, wherein the 5- to 10-membered aromatic rings and Ci-Cô linear, branched, and cyclic groups are optionally substituted with 1-4 substituents selected from halogens,

Ci-Cô linear, branched, and cyclic groups, and methoxy, and wherein an R^A group is optionally linked to an R^s group on an R² group;

(ii) R¹ is chosen from (a) hydrogen, ²⁰ (^b) Ci-C₈ linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, cyanoalkyl, hydroxy, alkyl sulfonyl, and

C|-Cô linear, branched, and cyclic groups, wherein the C[-Cô linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Ci-C₆ linear, branched, and cyclic groups are optionally substituted 30 with 1 -4 substituents independently chosen from halogens, hydroxy, and

C|-C₆ linear, branched, and cyclic alkoxy groups, (c) C|-C₈ linear, branched, and cyclic alkoxy or cyclic thioalkyl groups optionally substituted with 1-4 substituents independently chosen from halogens, cyano, cyanoalkyl, sulfone, sulfbnamide, hydroxy, and

Ci-Ce linear, branched, and cyclic alkyi groups that are optionally substituted with l-4 halogens or alkoxy groups;

O (d) O groups, wherein R is chosen from:

(aa) hydroxy, (bb) Ci-Cg linear, branched, and cyclic alkyi groups, wherein the alkyi group is optionally substituted with l-4 substituents independently chosen from halogens, cyano, hydroxy, and

C|-C₆ linear, branched, and cyclic groups, wherein the Ci-Cô linear, branched, and cyclic groups are independently chosen from alkyi and alkoxy groups, and wherein the Ci-C& linear, branched, and cyclic groups are optionally substituted with l-4 substituents independently chosen from halogens, hydroxy, and

C|-Q, linear, branched, and cyclic alkoxy groups, and (cc) C]-Cg linear, branched, and cyclic alkoxy groups optionally substituted with l-4 substituents independently chosen from halogens, cyano, hydroxy, and

C_rC₆ linear, branched, and cyclic alkyi groups that are optionally substituted with l-4 halogens;

O fs~N(R% <^e) ⁰ groups, wherein each R^D is independently chosen from (aa) hydrogen, (bb) C|-Cg linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with l-4 substituents independently chosen from halogens, cyano, hydroxy, and

Ci-Cé linear, branched, and cyclic groups, wherein the Ci-Ce linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the C_rCé linear, branched, and cyclic groups are optionally substituted with l-4 substituents independently chosen from 10 halogens, hydroxy, and

Ci-Cô linear, branched, and cyclic alkoxy groups, and (cc) C|-C₈ linear, branched, and cyclic alkoxy groups optionally substituted with 1 -4 substituents independently chosen from halogens, cyano, hydroxy, and Ci-C₆ linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 halogens, ²⁰ or two R^d groups together with the nitrogen atom to which they are bonded may form a

4-8 membered ring, optionally comprising one or two heteroatoms in addition to the nitrogen to which they are attached, and which ring is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and Ci-Q linear, branched, and cyclic groups, wherein the Ci-C^ linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the CpCé linear, branched, and cyclic groups are optionally ²⁰ substituted with 1-4 substituents independently chosen from halogens, hydroxy, and C[-C₆ linear, branched, and cyclic alkoxy groups;

r^e (f) groups, wherein R^E is chosen from:

(aa) hydrogen, (bb) Ci-Cg linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with l -4 substituents independently chosen from halogens, cyano, hydroxy, and

Ci-Cg linear, branched, and cyclic groups, wherein the Cj-Cg linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Cj-Cg linear, branched, and cyclic groups are optionally substituted with l -4 substituents independently chosen from halogens, hydroxy, and

Cj-Cg linear, branched, and cyclic alkoxy groups, (cc) Cj-Cs linear, branched, and cyclic alkoxy groups optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and

Cj-Cg linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 halogens;

(dd) 5- to 10-membered aromatic rings optionally substituted with 1-4 R^A, and (ee) C_rC₈ linear, branched, and cyclic aminoalkyl groups, and R¹' is chosen from:

(aa) hydroxy, (bb) Ci-C₈ linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and

C|-C₆ linear, branched, and cyclic groups, wherein the C]-C₆ linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the C|-Cô linear, branched, and cyclic groups are optionally substituted with l-4 substituents independently chosen from halogens, hydroxy, and Ci-C<, linear, branched, and cyclic alkoxy groups, and (cc) Ct-Cg linear, branched, and cyclic alkoxy groups optionally substituted with l-4 substituents independently chosen from halogens, cyano, hydroxy, and

C|-Cft linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 halogens;

O ^(CH^-P-R® (g) ^rG groups, wherein i is an integer ranging from 0 to 3 and each of R^G and R^c is independently chosen from (aa) hydroxy, (bb) Ci-C₈ linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and

C]-C₆ linear, branched, and cyclic groups, wherein the Ci-Q linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Cj-C₆ linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and Cj-Cé linear, branched, and cyclic alkoxy groups, and (cc) Ci-C₈ linear, branched, and cyclic alkoxy groups optionally substituted with 1 -4 substituents independently chosen from halogens, cyano, hydroxy, and

C|-C6 linear, branched, and cyclic alkyl groups that are optionally substituted with l -4 halogens, (dd) amino groups (ee) Ci-Cg linear, branched, and cyclic aminoalkyl groups, or R^g and R^G together with the phosphorous atom to which they are bonded may form a 4-8 membered ring, optionally comprising one or two heteroatoms in addition to the nitrogen to which they are attached, and which ring is optionally substituted wîth l-4 substituents independently chosen from halogens, cyano, hydroxy, and

Ci-C₆ linear, branched, and cyclic groups, wherein the Ci-C₆ linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Ci-C& linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and

C1-C& linear, branched, and cyclic alkoxy groups; and (h) ^wherein each of R^H is independently chosen from (aa) Ct-Cg linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and

C₍-C₆ linear, branched, and cyclic groups, wherein the Ci-Cé linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Ci-Cé linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and

C_rC₆ linear, branched, and cyclic alkoxy groups, and (bb) Ci-Cg linear, branched, and cyclic alkoxy groups optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and C|-Cs linear, branched, and cyclic alkyl groups that are optionally substituted with l-4 halogens;

(i) Ci-Cô alkylamide;

(iii) R² is chosen from 5- and 6-membered hetereocyclic rings (optionally substituted with oxo and/or C|-Cô linear and branched alkyl groups) and 5- to 6-membered aromatic rings comprising 0-4 heteroatoms chosen from O, N, and S, wherein the 5-membered aromatic ring is I0 optionally substituted with l-4 R^B groups and the 6-membered aromatic ring is optionally substituted with l-5 R^B groups, wherein the R^B groups are independently chosen from:

(a) amides, optionally substituted with 1-3 groups selected from C|-C<, linear, branched, and cyclic alkyl groups (optionally substituted with heteroaryl), 4- to 6-membered heterocyclyl (optionally substituted with oxo, C|-Cé linear, branched, and cyclic alkyl 15 groups, hydroxyalkyl, amide, alkyl sulfonyl, and acetamide); or wherein the amide nitrogen atom forms part of a 3- to 8-membered heterocyclyl ring (optionally substituted with alkylsulfonyl or Ci-Cô linear, branched, and cyclic alkyl groups), (b) imidazolidine-2,4-dione, (c) heterocyclyls optionally substituted with one more groups independently chosen from 20 oxo, acyl, and C|-Cô linear, branched, and cyclic alkyl groups (which is optionally further substituted with 1-3 groups independently chosen from oxo, hydroxy, and acyl), (d) phosphorous acid optionally esterified with a C_rC₆ linear, branched, or cyclic alkyl group, (e) di(C|-Cô)alkylphosphine oxides, (f) (Ci-C₆)alkylphosphinic acids optionally esterified with a Ci-Cô linear, branched, or cyclic alkyl group, (g) halogens, (h) cyano, (i) hydroxy, (j) carboxylic acids optionally esterified with a uronic acid or a C₍-C₆ linear, branched, or cyclic alkyl group, (k) oxo, (1) -BiOR’h groups, wherein each R¹ is independently chosen from hydrogen and C_rC₆ linear, branched, and cyclic alkyl groups, or two OR¹ groups together with the boron atom to 35 which they are bonded may fbrm a 4-8 membered ring, optionally comprising one or two heteroatoms in addition to the nitrogen to which they are attached, and which ring is optionally substituted with l-4 substituents independently chosen from halogens, cyano, hydroxy, and

Cj-C₆ linear, branched, and cyclic groups, wherein the C]-C₆ linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Ci-C₆ linear, branched, and cyclic groups are optionally substituted with l-4 substituents independently chosen from halogens, hydroxy, and

C[-C₆ linear, branched, and cyclic alkoxy groups, (m) 5- and 6-membered aromatic rings comprising 0-4 heteroatoms independently chosen from O, N, and S, optionally substituted with i or 2 substituents independently chosen from C_r

C₆ linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 substituents independently chosen from hydroxy, carboxylic acids, pyrrolidin-2-one,

C,-C₆ linear, branched, and cyclic alkyl groups, and

Ci-Cè linear, branched, and cyclic alkylsulfonyl groups, and

Ci-C₆ linear, branched, and cyclic alkoxy groups, (n) sulfonic acid,

O

4-s-r^{j c} II (ο) o groups, wherein R'¹ is chosen from:

(aa) hydroxy, (bb) Ci-C₈ linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, 30 hydroxy, and

Cj-Cô hnear, branched, and cyclic groups, wherein the CpCe linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Ci-C₆ linear, branched, and cyclic groups are optionally substituted with I-4 substituents independently chosen from halogens, hydroxy, Ci-C₆ linear, branched, and cyclic alkoxy groups, heterocyclyl optionally substituted with oxo, and amide (cc) C|-Cg linear, branched, and cyclic alkoxy groups optionally substituted with I -4 substituents independently chosen from halogens, cyano, hydroxy, and

Ci-Cé linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 halogens (dd) 5- to 10-membered aromatic rings optionally substituted with 1-4 R^A, and (ee) C|-C₈ linear, branched, and cyclic aminoalkyl groups, O

4s-N(R*)₂ (p) ° groups, wherein each R^K is independently chosen from:

(aa) hydrogen, (bb) Ci-C₈ linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and

C]-C₆ linear, branched, and cyclic groups, wherein the Ci-C₆ linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the C_rC₆ linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and

Ci-C₆ linear, branched, and cyclic alkoxy groups, and (cc) C_t-C₈ linear, branched, and cyclic alkoxy groups optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and

C[-C₆ linear, branched, and cyclic alkyl groups that are optionally substituted with l-4 halogens, or two R^K groups together with the nitrogen atom to which they are bonded may form a 4-8 membered ring, optionally comprising one or two heteroatoms in addition to the nitrogen to which they are attached, and which ring is optionally substituted with l-4 substituents independently chosen from halogens, cyano, hydroxy, and Ci-Cg linear, branched, and cyclic groups, wherein the Ci-Cg linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the C|-C₆ linear, branched, and cyclic groups are optionally substituted with l-4 substituents independently chosen from halogens, hydroxy, and

Ci-Cg linear, branched, and cyclic alkoxy groups

O

-|“P-R^L (q) ^rL groups, wherein each ofR^L and R^L’ is independently chosen from (aa) hydroxy, (bb) Ci-Cg linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with l-4 substituents independently chosen from halogens, cyano, hydroxy, and

Ci-Cg linear, branched, and cyclic groups, wherein the Ci-C₆ linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Cj-C^ linear, branched, and cyclic groups are optionally substituted with 1 -4 substituents independently chosen from halogens, hydroxy, and

Ci-Cô linear, branched, and cyclic alkoxy groups, and (cc) Cj-Cg linear, branched, and cyclic alkoxy groups optionally substituted with l-4 substituents independently chosen from halogens, cyano, hydroxy, and

C1-C5 linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 halogens, (dd) amino groups (ee) Cj-Cg linear, branched, and cyclic aminoalkyl groups, or R^l and R^L together with the phosphorous atom to which they are bonded may form a 4-8 membered ring, optionally comprising one or two heteroatoms in addition to the nitrogen to which they are attached, and which ring is optionally substituted with 1 -4 substituents independently chosen from halogens, cyano, hydroxy, and Cj-Cô linear, branched, and cyclic groups, wherein the Ci-Cô linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Ci-Cô linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and C|-Cô linear, branched, and cyclic alkoxy groups, (r) C]-C₆ linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, carboxylîc acid, C|-C₆ linear, branched, and cyclic alkoxy groups, heterocyclyl optionally substituted with oxo, and amide, (s) C|-Cô linear, branched, and cyclic alkoxy groups that are optionally substituted with 1 -4 substituents independently chosen from halogens, hydroxy, 13 carboxylic acid,

Ci-Cg linear, branched, and cyclic alkyl groups, and

C|-Cb linear, branched, and cyclic alkoxy groups, and n-n vV (t) groups, wherein R^M is chosen from:

(aa) hydrogen, (bb) carboxylic acid, (cc) Ci-Ce linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with l-4 substituents independently chosen from halogens, cyano, hydroxy, and Ci-Cô linear, branched, and cyclic groups, wherein the Ci-Cô linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Ci-C& linear, branched, and cyclic groups are optionally substituted with l -4 substituents independently chosen from halogens, hydroxy, and

C|-C₆ linear, branched, and cyclic alkoxy groups, (dd) Cj-C_s linear, branched, and cyclic alkoxy groups optionally substituted with l-4 substituents independently chosen from halogens, cyano, hydroxy, and

C_rC₆ linear, branched, and cyclic alkyl groups that are optionally substituted with l-4 halogens (ee) 5- to l O-membered aromatic rings optionally substituted with l -4 R^A (ff) halogens (gg) hydroxy (u) O-Rⁿ wherein R^N is chosen from (aa) Ci-Cj linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with l-4 substituents independently chosen from halogens, cyano, hydroxy, and

Cj-Cô linear, branched, and cyclic groups, wherein the Ci-Cô linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Ci-Cô linear, branched, and cyclic groups are optionally substituted with l-4 substituents independently chosen from halogens, hydroxy, and

Ci-Cô linear, branched, and cyclic alkoxy groups, and (bb) C|-C_s linear, branched, and cyclic alkoxy groups optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and C|-Cô linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 halogens,

O (v) ^(R°)2, wherein each R° is independently chosen from hydrogen and a C_rC_s linear, branched, and cyclic alkyl group, wherein the alkyl group is optionally substituted with 14 substituents independently chosen from alkylsulfonyl, alkylamîde, halogens, cyano, hydroxy, and

C_rC₆ linear, branched, and cyclic groups, wherein the C_rC₆ linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the C]-C₆ linear, branched, and cyclic groups are optionally substituted with 1 -4 substituents independently chosen from halogens, hydroxy, and

Ci-C₆linear, branched, and cyclic alkoxy groups, or two R° groups together with the nitrogen atom to which they are bonded may form a 4-8 membered ring, optionally comprising one or two heteroatoms in addition to the nitrogen to which they are attached, and which ring is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and Ci-Cô linear, branched, and cyclic groups, wherein the Ci-Cô linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Cj-Q linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and

Ci-C₆ linear, branched, and cyclic alkoxy groups, and

(w) , wherein Y; is chosen from oxygen, N-R^p, and N R^p, wherein R^p is chosen from a CpCg linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1 -4 substituents independently chosen from halogens, cyano, hydroxy, and

C|-C6 linear, branched, and cyclic groups, wherein the Ci-Ce linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Ci-Cô linear, branched, and cyclic groups are optionally substituted with 1 -4 substituents independently chosen from halogens, hydroxy, and Ci-C_b linear, branched, and cyclic alkoxy groups, wherein 2 adjacent hydrogens on the 5- or 6-membered aromatic ring can be replaced by attachments to a second 5- or 6-membered aromatic ring comprising 0-4 heteroatoms independently chosen from O, N, and S to form a bicyclic R² group that is optionally substituted with 1-6 R^b groups;

(iv) X¹ and X² are independently chosen from hydrogen, halogens, cyano, hydroxy, Ci-C₆ linear, branched, and cyclic groups wherein the C_rC₆ linear, branched, and cyclic groups are independently chosen from alkyl, alkoxy, thioalkyl, and aminoalkyl groups, and wherein the C_r Cû linear, branched, and cyclic groups are optionally substituted by 1-4 independently chosen halogens;

(v) each of W¹ and W² is independently selected from C and N;

(vi) each —' — - represents a single or double bond, provided that no more than one---is a double bond;

(vii) each R³ is independently chosen from hydrogen, halogens, cyano, CpCé linear, branched, and cyclic alkyl groups, and Ci-Cé linear, branched, and cyclic alkoxy groups, wherein the Ci-C₆ linear, branched, and cyclic alkyl groups and the Cj-C₆ linear, branched, and cyclic alkoxy groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy groups, and carboxylic acid;

(viii) n is an integer chosen from 0, 1,2, and 3; and (ix) Z¹, Z², and Z³ are independently chosen from carbon, boron, nitrogen, sulfur, and oxygen, wherein when Z¹, Z², and/or Z³ are carbon or nitrogen, the valences of carbon and nitrogen are completed with hydrogen atoms, halogen, Cj-Cô linear, branched, and cyclic alkyl groups, and Cj-Cô linear, branched, and cyclic alkoxy groups, wherein the Ci-C& linear, branched, and cyclic alkyl groups and the Cj-Cô linear, branched, and cyclic alkoxy groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy groups, and carboxylic acid, and wherein when Z¹, Z², or Z³ is boron, the valence of boron is completed with a hydrogen atom or a hydroxy group.

In one aspect of the invention the compounds of Formula I are selected from Compounds 1-342, as well as tautomers of those compounds, pharmaceutically acceptable salts of those compounds and their tautomers, and deuterated derivatives of any of the foregoing that can be employed in the treatment of AATD.

In some embodiments, the invention provides pharmaceutical compositions comprising at least one compound of selected from compounds of Fonnulae I, T-A, I-B, I-C, I-D, I-E, I-F, ΙΟ, and I-H and tautomers of those compounds, pharmaceutically acceptable salts of those compounds and their tautomers, and deuterated derivatives of any of the foregoing. In spécifie embodiments, the pharmaceutical compositions may comprise a compound selected from Compounds 1-342, tautomers of those compounds, pharmaceutically acceptable salts of those compounds and their tautomers, and deuterated derivatives of any of the foregoing. These compositions may further include at least one additional active pharmaceutical ingrédient and/or at least one carrier.

Another aspect of the invention provides methods of treating AATD comprising administering to a subject in need thereof, at least one compound of selected from compounds of Fonnulae I, I-A, I-B, I-C, I-D, I-E, I-F, I-G, and I-H and tautomers of those compounds, pharmaceutically acceptable salts of those compounds and their tautomers, and deuterated derivatives of any of the foregoing or a pharmaceutical composition comprising the at least one compound. In spécifie embodiments, the methods comprise administering a compound selected from Compounds 1-342, tautomers of those compounds, pharmaceutically acceptable salts of those compounds and their tautomers, and deuterated dérivatives of any ofthe foregoing.

In some embodiments, the methods of treatment include administration of at least one additional active agent to the subject in need thereof, either in the same pharmaceutical composition as the at least one compound of selected from compounds of Formulae I, I-A, I-B, I-C, I-D, I-E, I-F, I-G, and I-H tautomers of those compounds, pharmaceutically acceptable salts of those compounds and their tautomers, and deuterated dérivatives of any of the foregoing, or as separate compositions. In spécifie embodiments, the methods comprise administering a compound selected from Compounds 1-342, tautomers of those compounds, pharmaceutically acceptable salts of those compounds and their tautomers, and deuterated dérivatives of any of the foregoing with at least one additional active agent either în the same pharmaceutical composition or in a separate composition. In some embodiments, the subject in need of treatment carries the ZZ mutation. In some embodiments, the subject in need of treatment carries the SZ mutation.

Also provided are methods of modulating AAT, comprising administering to a subject in need thereof, at least one compound of selected from compounds of Formulae I, I-A, I-B, I-C, ΙΟ, I-E, I-F, I-G, and I-H and tautomers of those compounds, pharmaceutically acceptable salts of those compounds and their tautomers, and deuterated dérivatives of any of the foregoing or a pharmaceutical composition comprising the at least one compound, tautomer, sait, or deuterated derîvative. In spécifie embodiments, the methods of modulating AAT comprise administering at least one compound selected from Compounds 1-342, tautomers of those compounds, pharmaceutically acceptable salts of those compounds and their tautomers, and deuterated dérivatives of any of the foregoing or a pharmaceutical composition comprising the at least one compound, tautomer, sait, or deuterated dérivative.

Brief Description of the Drawings

FIG. IA shows an XRPD diffractogram of Compound 33 Form A.

FIG. IB shows a solid State ^l3C NMR spectrum of Compound 33 Form A.

FIG. IC shows a solid state ^l9F NMR spectrum of Compound 33 Form A.

FIG. ID shows a TGA thermogram of Compound 33 Form A.

FIG. IE shows a DSC thermogram of Compound 33 Form A.

FIG. 1F shows an IR spectrum of Compound 33 Form A.

FIG. 2A shows an XRPD diffractogram of Compound 33 Form B.

FIG. 2B shows a solid state ^l3C NMR spectrum of Compound 33 Form B.

FIG. 2C shows a solid state ^I9F NMR spectrum of Compound 33 Form B.

FIG. 2D shows a TGA thermogram of Compound 33 Form B.

FIG. 2E shows a DSC thermogram of Compound 33 Form B.

FIG. 3A shows an XRPD diffractogram of Compound 33 DCM solvaté Form A.

FIG. 3B shows a TGA thennogram of Compound 33 DCM solvaté Form A.

FIG. 3C shows a DSC thermogram of Compound 33 DCM solvaté Form A.

FIG. 4 A shows an XRPD diffractogram of Compound 33 hydrate Form A.

FIG. 4B shows a solid state ^l3C NMR spectrum of Compound 33 hydrate Form A.

FIG. 4C shows a solid state ^l9F NMR spectrum of Compound 33 hydrate Form A.

FIG. 4D shows a TGA thermogram of Compound 33 hydrate Form A.

FIG. 4E shows a DSC thennogram of Compound 33 hydrate Form A.

FIG. 5A shows an XRPD diffractogram of Compound 33 MeOH/FBO solvate/hydrate Form A.

FIG. 5B shows a TGA thennogram of Compound 33 MeOH/EEO solvate/hydrate Form A.

FIG. 5C shows a DSC thermogram of Compound 33 MeOH/H₂O solvate/hydrate Fonn A.

FIG. 6A shows an XRPD diffractogram of Compound 33 Form C.

FIG. 7A shows an XRPD diffractogram of Compound 33 Fonn D.

FIG. 7B shows a TGA thermogram of Compound 33 Form D.

FIG. 7C shows a DSC thennogram of Compound 33 Form D.

FIG. SA shows an XRPD diffractogram of Compound 33 Form E.

FIG. 9 A shows an XRPD diffractogram of Compound 33 Form F.

FIG. 9B shows a TGA thennogram of Compound 33 Form F.

FIG. 9C shows a DSC thermogram of Compound 33 Fonn F.

FIG. 10A shows an XRPD diffractogram of Compound 33 Form G.

FIG. 10B shows a TGA thennogram of Compound 33 Form G.

FIG. 10C shows a DSC thermogram of Compound 33 Fonn G.

FIG. 11A shows an XRPD diffractogram of Compound 33 Form H.

FIG. 1 IB shows a TGA thermogram of Compound 33 Form H.

FIG. 1 IC shows a DSC thermogram of Compound 33 Fonn H.

FIG. 12A shows an XRPD diffractogram of Compound 33 having been initially reacted with EtOH.

FIG. 12B shows an XRPD diffractogram of Compound 33 having been reacted with EtOH ovemight.

FIG. 12C shows an XRPD diffractogram of Compound 33 Form I.

FIG. 12D shows a TGA thermogram of Compound 33 Form I.

FIG. 12E shows a DSC thermogram of Compound 33 Form 1.

FIG. I3A shows an XRPD diffractogram of Compound 33 THF solvaté Fonn A.

FIG. I3B shows a solid State ^l3C NMR spectrum of Compound 33 THF solvaté Form A.

FIG. 13C shows a solid State ^l9F NMR spectrum of Compound 33 THF solvaté Form A.

FIG. 13D shows a TGA thermogram of Compound 33 THF solvaté Form A.

FIG. 13E shows a DSC thermogram of Compound 33 THF solvaté Form A.

FIG. 14A shows an XRPD diffractogram of Compound 33 Form J.

FIG. 14B shows a TGA thermogram of Compound 33 Form J.

FIG. 15A shows an XRPD diffractogram of Compound 33 Form K.

FIG. 15B shows a TGA thermogram of Compound 33 Form K.

FIG. 15C shows a DSC thermogram of Compound 33 Form K.

FIG. 16A shows an XRPD diffractogram of Compound 33 2-MeTHF solvaté Form A.

FIG. 16B shows a TGA thermogram of Compound 33 2-MeTHF solvaté Form A.

FIG. 16C shows a DSC thermogram of Compound 33 2-MeTHF solvaté Form A.

FIG. 17 A shows an XRPD diffractogram of Compound 33 Form L.

FIG. 17B shows a TGA thermogram of Compound 33 Form L.

FIG. 17C shows a DSC thermogram of Compound 33 Form L.

FIG. 18A shows an XRPD diffractogram of Compound 33 Form M.

FIG. 18B shows a TGA thermogram of Compound 33 Form M.

FIG. 18C shows a DSC thermogram of Compound 33 Form M.

FIG. 19A shows an XRPD diffractogram of Compound 33 Form N.

FIG. 19B shows a TGA thermogram of Compound 33 Form N.

FIG. 19C shows a DSC thermogram of Compound 33 Form N.

FIG. 20A shows an XRPD diffractogram of Compound 33 Form O.

FIG. 20B shows a TGA thermogram of Compound 33 Form O.

FIG. 2lA shows an XRPD diffractogram of Compound 33 K sait Form A.

FIG. 21B shows a TGA thermogram of Compound 33 K sait Form A.

FIG. 2IC shows a DSC thermogram of Compound 33 K sait Form A.

FIG. 22A shows an XRPD diffractogram of Compound 33 K sait Form B.

FIG. 22B shows a TGA thermogram of Compound 33 K sait Form B.

FIG. 22C shows a DSC thermogram of Compound 33 K sait Form B.

FIG. 23A shows an XRPD diffractogram of Compound 33 K sait Form C.

FIG. 23B shows a TGA thermogram of Compound 33 K sait Form C.

FIG. 23C shows a DSC thermogram of Compound 33 K sait Form C.

FIG. 24A shows an XRPD diffractogram of Compound 33 50%DL Amorphous Spray Dried

Dispersion [DCM/EtOH/10%Water with HPMCAS-H].

FIG. 24B shows a DSC thermogram of Compound 33 50%DL Amorphous Spray Dried

Dispersion [DCM/EtOH/l 0%Water with HPMCAS-H].

FIG. 24C shows a TGA thermogram of Compound 33 50%DL Amorphous Spray Dried Dispersion [DCM/EtOH/lO%Water with HPMCAS-H].

FIG. 25A shows an XRPD diffractogram of Compound 33 50%DL Amorphous Spray Dried Dispersion [DCM/EtOH/lO% Water with PVPVA],

FIG. 25B shows a DSC thermogram of Compound 33 50%DL Amorphous Spray Dried Dispersion [DCM/EtOH/lO%Water with PVPVA].

FIG. 26A shows an XRPD diffractogram of Compound 33 50%DL Amorphous Spray Dried Dispersion [DCM/EtOH/lO%Water with HPMC El5].

FIG. 26B shows a DSC thermogram of Compound 33 50%DL Amorphous Spray Dried

Dispersion [DCM/EtOH/lO%Water with HPMC E15],

FIG. 27A shows an XRPD diffractogram of Compound 33 50%DL Amorphous Spray Dried Dispersion [DCM/EtOH/1% Water with HPMCAS-H],

FIG. 27B shows a DSC thermogram of Compound 33 50%DL Amorphous Spray Dried Dispersion [DCM/EtOH/l %Water with HPMCAS-H],

FIG. 27C shows a TGA thermogram of Compound 33 50%DL Amorphous Spray Dried Dispersion [DCM/EtOH/1% Water with HPMCAS-H],

FIG. 28A shows an XRPD diffractogram of Compound 33 50%DL Amorphous Spray Dried Dispersion [DCM/EtOH/l%Water with HPMCAS-H],

FIG. 28B shows a DSC thermogram of Compound 33 50%DL Amorphous Spray Dried Dispersion [DCM/EtOH/l%Water with HPMCAS-H],

FIG. 28C shows a TGA thermogram of Compound 33 50%DL Amorphous Spray Dried Dispersion [DCM/EtOH/l%Water with HPMCAS-H],

FIG. 29A shows an XRPD diffractogram of Compound 33 50%DL Amorphous Spray Dried Dispersion [DCM/EtOH/l %Water with HPMCAS-H].

FIG. 29B shows a DSC thermogram of Compound 33 50%DL Amorphous Spray Dried Dispersion [DCM/EtOH/l%Water with HPMCAS-H].

FIG. 3OA shows an XRPD diffractogram of Compound 33 50%DL Amorphous Spray Dried Dispersion [THF/Water with HPMCAS-H].

FIG. 30B shows a DSC thermogram of Compound 33 50%DL Amorphous Spray Dried Dispersion [THF/Water with HPMCAS-H].

FIG. 30C shows a TGA thermogram of Compound 33 50%DL Amorphous Spray Dried Dispersion [THF/Water with HPMCAS-H],

FIG. 30D shows a solid state ⁱ³C NMR spectrum of a spray dried dispersion of 50% Compound 33 with HPMCAS.

FIG. 30E shows a solid State ^l9F NMR spectrum of a spray dried dispersion of 50% Compound 33 with HPMCAS.

FIG. 31A shows an XRPD diffractogram of Compound 33 50%DL Amorphous Spray Dried

Dispersion [2-MeTHF/EtOH/Water with HPMCAS-H].

FIG. 31B shows a DSC thermogram of Compound 33 50%DL Amorphous Spray Dried

Dispersion [2-MeTHF/EtOH/Water with HPMCAS-H].

FIG. 31C shows a TGA thermogram of Compound 33 50%DL Amorphous Spray Dried

Dispersion [2-MeTHF/EtOH/Water with HPMCAS-H].

FIG. 32A shows an XRPD diffractogram of Compound 33 80%DL Amorphous Spray Dried

Dispersion [DCM/EtOH/Water with HPMCAS-H].

FIG. 32B shows a DSC thermogram of Compound 33 80%DL Amorphous Spray Dried

Dispersion [DCM/EtOH/Water with HPMCAS-H].

FIG. 32C shows a TGA thermogram of Compound 33 80%DL Amorphous Spray Dried Dispersion [DCM/EtOH/Water with HPMCAS-H],

FIG. 33A shows an XRPD diffractogram of Compound 33 80%DL Amorphous Spray Dried

Dispersion [DCM/EtOH/Water with HPMCAS-H, starting with THF Solvaté DS].

FIG. 33B shows a DSC thermogram of Compound 33 80%DL Amorphous Spray Dried

Dispersion [DCM/EtOH/Water with HPMCAS-H, starting with THF Solvaté DS].

FIG. 34A shows an XRPD diffractogram of Compound 33 80%DL Amorphous Spray Dried

Dispersion [THF/Water with HPMCAS-H],

FIG. 34B shows a DSC thermogram of Compound 33 80%DL Amorphous Spray Dried

Dispersion [THF/Water with HPMCAS-H],

FIG. 34C shows a solid state C NMR spectrum of a spray dried dispersion of 80% Compound 33 with HPMCAS.

FIG. 34D shows a solid state ^l9F NMR spectrum of a spray dried dispersion of 80% Compound 33 with HPMCAS.

FIG. 35A shows an XRPD diffractogram of Compound 33 80%DL Amorphous Spray Dried Dispersion [THF/Water with PVPVA],

FIG. 35B shows a DSC thermogram of Compound 33 80%DL Amorphous Spray Dried Dispersion [THF/Water with PVPVA],

FIG. 36A shows an XRPD diffractogram of Compound 33 80%DL Amorphous Spray Dried Dispersion [THF/Water with HPMC El5],

FIG. 36B shows a DSC thermogram of Compound 33 80%DL Amorphous Spray Dried Dispersion [THF/Water with HPMC El5].

FIG. 37A shows an XRPD diffractogram of Compound 33 80%DL Amorphous Spray Dried Dispersion [2-MeTHF/EtOH/Water with HPMCAS-H].

FIG. 37B shows a DSC thermogram of Compound 33 80%DL Amorphous Spray Dried Dispersion [2-MeTHF/EtOH/Water with HPMCAS-H].

FIG. 37C shows a TGA thermogram of Compound 33 80%DL Amorphous Spray Dried Dispersion [2-MeTHF/EtOH/Water with HPMCAS-H],

FIG. 38A shows an XRPD diffractogram of Spray-Dried Neat Amorphous Compound 33 [DCM/EtOH/Water without polymer],

FIG, 38B shows a DSC thermogram of Spray-Dried Neat Amorphous Compound 33 [DCM/EtOH/Water without polymer],

FIG. 38C shows a solid state ^l3C NMR spectrum of neat amorphous Compound 33.

FIG. 38D shows a solid state ^l9F NMR spectrum of neat amorphous Compound.

Detaiied Description

I. Définitions

The tenu AAT as used herein means alpha-1 antitrypsin or a mutation thereof, including, but not limited to, the AAT gene mutations such as Z mutations. As used herein, “Z-AAT” means AAT mutants which hâve the Z mutation.

The term “AATD” as used herein means alpha-1 antitrypsin deficiency, which is a genetic disorder characterized b y low circulating levels of AAT.

The tenu “compound,” when referring to a compound of this disclosure, refers to a collection of molécules having an identical Chemical structure unless otherwise indicated as a collection of stereoisomers (for ex ample, a collection of racemates, a collection of cis/trans stereoisomers, or a collection of (E) and (Z) stereoisomers), except that there may be isotopic variation among the constituent atoms of the molécules. Thus, it will be clear to those of skill in the art that a compound represented by a particular Chemical structure containing indicated deuterium atoms, will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure. The relative amount of such isotopologues in a compound of this disclosure will dépend upon a number of factors including the isotopic purity of reagents used to make the compound and the efficiency of incorporation of isotopes in the various synthesis steps used to préparé the compound. However, as set forth above the relative amount of such isotopologues in toto will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopologues in toto will be 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.

Compounds of the invention may optionally be substituted with one or more substituents. It will be appreciated 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 or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an “optionally substituted” group may hâve a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent chosen from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are those that resuit in the formation of stable or chemicalîy feasible compounds.

The tenn “isotopologue” refers to a species in which the Chemical structure differs from a spécifie compound of this disclosure only in the îsotopic composition thereof. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³C or ^l4C are within the scope of this disclosure.

Unless otherwise indicated, structures depicted herein are also meant to include ail isomeric forms of the structure, e.g., racemic mixtures, atropisomers, diastereomeric mixtures, cis/trans isomers, géométrie (or conformationai) isomers, such as (Z) and (E) double bond isomers, and (Z) and (A) conformationai isomers. Therefore, géométrie and conformationai mixtures of the present compounds are within the scope of the disclosure. Unless otherwise stated, ail tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.

The term “tautomer,” as used herein, refers to one of two or more isomers of a compound that exist together in equilibrium and are readily interchanged by migration of an atom or group within the molécule.

“Stereoisomer” refers to both enantiomers and diastereomers.

As used herein, “deuterated dérivative” refers to a compound having the same Chemical structure as a reference compound, but with one or more hydrogen atoms replaced by a deuterium atom (“D”). It will be recognîzed that some variation of natural isotopic abundance occurs in a synthesized compound depending on the origin of Chemical materials used in the synthesis. The concentration of naturally abundant stable hydrogen isotopes, notwithstanding this variation is small and immaterial as compared to the degree of stable isotopic substitution of deuterated derivatives described herein. Thus, unless otherwise stated, when a reference is made 24 to a “deuterated dérivative” of a compound of the invention, at least one hydrogen is replaced with deuterium at well above its natural isotopîc abundance (which is typically about 0,015%). In some embodiments, the deuterated dérivatives of the invention hâve 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 lease 6333.3 (95% deuterium incorporation, at least 6466.7 (97% deuterium incorporation, or at least 6600 (99% deuterium incorporation).

The term “isotopic enrichment factor” as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

The term alkyl,” or “aliphatic” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completel y saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic that has a single point of attachment to the rest of the molécule. 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, în other embodiments alkyl groups contain 1-4 alkyl carbon atoms, and in yet other embodiments alkyl groups contain 1-3 alkyl carbon atoms. Nonlimiting examples of alkyl groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. Suitable cycloaliphatic groups include cycloalkyl, bicyclic cycloalkyl (e.g., decalin), bridged bicycloalkyl such as norbomy] or [2.2.2]bicycio-octyl, or bridged tricyclic such as adamantyl.

The terms cycloalkyl, carbocycle, cycloaliphatic, or “cyclic alkyl” refer to a spirocyclic or monocyclic Cj__s hydrocarbon or a spirocyclic, bicyclic, bridged bicyclic, tricyclic, or bridged tricyclic C₈_j₄ hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, wherein any individual ring in said bicyclic ring system has 3-7 members.

The tenu heteroalkyl, or “heteroaliphatic” as used herein, means aliphatic groups wherein one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or Silicon. Heteroaliphatic groups may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include heterocycle, heterocyclyl, heterocycloaliphatic, or heterocyciic groups.

The term “alkenyl” as used herein, means a straight-chain (i.e., unbranched), branched, substituted or unsubstituted hydrocarbon chain that contains one or more units of saturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that contains one or more units of unsaturation, but which is not aromatic (referred to herein as, “cyclic alkenyl”).

The tenu heterocycle, heterocyclyl, heterocycloaliphatîc, or heterocyclic as used herein means non-aromatic, monocyclic, bicyclic, or tricyclic ring Systems in which one or more ring members is an independently chosen heteroatom. In some embodiments, the heterocycle, heterocyclyl, heterocycloaliphatîc, or heterocyclic group has three to fourteen ring members in which one or more ring members is a heteroatom independently chosen from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3 to 7 ring members.

The term heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or Silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or Silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as in N-substituted pyrrolîdinyl)).

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

The term alkoxy, or thioalkyl, as used herein, refers to an alkyl group, as prevîously defined, wherein one carbon of the alkyl group is replaced by an oxygen (alkoxy) or sulfur (thioalkyl) atom, respectiveîy, provided that the oxygen and sulfur atoms are linked between two carbon atoms. A “cyclic alkoxy” refers to a monocyclic, spirocyclic, bicyclic, bridged bicyclic, tricyclic, or bridged tricyclic hydrocarbon that contains at least one alkoxy group, but is not aromatic. Non-limiting examples of cyclic alkoxy groups include tetrahydropyranyl, tetrahydro furanyl, oxetanyl, 8-oxabtcyclo[3.2.l]octanyl, and oxepanyl, A “cyclic thioalkyl” refers to a monocyclic, spirocyclic, bicyclic, bridged bicyclic, tricyclic, or bridged tricyclic hydrocarbon that contains at least one thioalkyl group, but is not aromatic.

The terms haloalkyl and haloalkoxy means an alkyl or alkoxy, as the case may be, which is substituted with one or more halogen atoms. The term halogen or means F, Cl, Br, or I. Examples of haloalkyls include -CHF₂, -CH₂F, -CF₃, -CF₂-, or perhaloalkyl, such as, -CF₂CF₃.

The term “aminoalkyl” means an alkyl group which is substituted with or contains an amino group. As used herein, an “amino” refers to a group which is a primary, secondary, or tertiary amine.

The term “alkylsulfoxide” means an alkyl group in which a carbon of said alkyl group is replaced by or substituted with a sulfoxide group. A “cyclic alkylsulfoxide” refers to a monocyclic hydrocarbon or bicyclic hydrocarbon that contains one or more alkylsulfoxides, but 26 is not aromatic. As used herein, “sulfoxide” means a sulfïnyl (i.e., -S(O)-) which is attached to two carbon atoms.

The term “alkylsulfinamide” means an alkyl group in which a carbon of said alkyl group is replaced by or substituted with a sulfmamide group. As used herein, “sulfmamide” refers to -S(O)-, in which the sulfur atom is independently attached to an amine group and attached to carbon.

The term “alkyl sulfonyl” means an alkyl group in which a carbon of said alkyl group is replaced by or substituted with a sulfonyl group. As used herein, “sulfonyl” refers to -S(O)2-, wherein the sulfur is attached to a carbon and also attached to a different carbon.

The term “alkylsulfonamide” means an alkyl group in which a carbon of said alkyl group îs replaced b y or substituted with a sulfonamide group. As used herein, a “sulfonamide” refers to a -S(O)₂- wherein the sulfur is attached to an amine group and also attached to carbon.

The term “alkylamide” means an alkyl group in which a carbon of said alkyl group is replaced with an amide. As used herein, “amide” refers to a carbonyl (i.e., -C(O)-) that is attached to an amine group and also attached to carbon. An optionally substituted amide may be mono- or di-substituted at the amide nitrogen. Altematively, or in addition, an optionally substituted amide may be substituted at the carbonyl carbon.

As used herein, an oxo group refers to =O.

As used herein, a “cyano” or “nitrile” groups refers to -ON.

As used herein, a “hydroxy” group refers to -OH.

“Tert” and “t-” each refer to tertiary.

As used herein, “aromatic groups” or “aromatic rings” refer to Chemical groups that contain conjugated, planar ring Systems with delocalized pi électron orbitals comprised of [4n+2] p orbital électrons, wherein n is an integer ranging from 0 to 6. Nonlimiting examples of aromatic groups include aryl and heteroaryl groups.

The term aryl used alone or as part of a larger moiety as in arylalkyl, arylalkoxy, or aryloxyalkyl, refers to monocyclic, bicyclic, and tricyclic ring Systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term aryl also refers to heteroaryl ring Systems as defined herein below. Nonlimiting examples of aryl groups include phenyl rings.

The term heteroaryl, used alone or as part of a larger moiety as in heteroaralkyl or heteroarylalkoxy, refers to monocyclic, bicyclic, and tricyclic ring Systems having a total of five to fourteen 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 wherein each ring in the System contains 3 to 7 ring members.

An aryl (includîng arylalkyl, arylalkoxy, aryloxyalkyl and the like) or heteroaryl (includîng heteroarylalkyl and heteroarylalkoxy and the like) group may contain one or more substituents.

An alkyl group, or a non-aromatic heterocyclic ring may contain one or more substituents.

Examples of useful protecting groups for nitrogen-containing groups, such as amine groups, include, for example, t-butyl carbamate (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9fluoren y l methyl carbamate (Fmoc) benzyl carbamate (Cbz), acetamide, trîfluoroacetamide, triphenylmethyl amine, benzylideneamîne, and p-toluenesulfonamide. Methods of adding (a process generally referred to as protecting”) and removing (process generally referred to as deprotecting) such amine protecting groups are well-known in the art and available, for example, in P. J. Kocienski, Protecting Groups, Thieme, 1994, which is hereby incorporated by reference in its entîrety and in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition (John Wiley & Sons, New York, 1999).

Examples of suitabie solvents that may be used in this disclosure include, but not limited to, water, methanol (MeOH), éthanol (EtOH), dichloromethane or “methylene chloride” (CH2CI2), toluene, acetonitrile (MeCN), dimethylfomiamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptanes, isopropyl acetate (IPAc), tert-buty! acetate (tBuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2-Me THF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et20), methyl-tert-butyl ether (MTBE), 1,4-dioxane, and 7V-methyl pyrrolidone (NMP).

Examples of suitabie bases that may be used in this disclosure include, but not limited to, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (K₂CO₃), A-methylmorpholine (N MM), triethylamine (EtjN; TE A), diisopropyl-ethyl amine (i-Pr₂EtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH) and sodium methoxide (NaOMe; NaOCHj).

The disclosure includes pharmaceutically acceptable salts of the compounds ofthe invention, A sait of a compound of is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group.

The terni “phannaceutically acceptable,” as used herein, refers to a component that is, within the scope of sound medical judgment, suitabie for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergie response and the like, and are commensurate with a reasonable benefit/risk ratio. A “pharmaceutically acceptable sait” means any non-toxic sait that, upon administration to a récipient, is capable of providing, either directly or indirectly, a compound of this disclosure. Suitabie phannaceutically acceptable salts are, for example, those disclosed in S. M. Berge, étal. J. Pharmaceutical Sciences, 1977, 66, 1-19.

Actds commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfurie acid and phosphoric acid, as well as organic acids such as para-toluenesidfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonîc acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, βhydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalenel-sulfonate, naphthalene-2-suIfonate, mandelate and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include those formed with minerai acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

Pharmaceutically acceptable salts derived from appropriate bases include alkali métal, alkaline earth métal, ammonium, and N⁺(CMalkyl)₄ salts. This disclosure also envisîons the quatemization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth métal salts include sodium, lithium, potassium, calcium, and magnésium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quatemary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

The terms “patient” and “subject” are used interchangeably and refer to an animal including a human.

The terms effective dose and effective amount are used interchangeably herein and refer to that amount of a compound that produces the desired effect for which it is administered (e.g., improvement in AATD or a symptom of AATD, lessening the severity of AATD or a symptom of AATD, and/or reducing the rate of onset or incidence of AATD or a symptom of AATD). The exact amount of an effective dose will dépend on the purpose of the treatment, and will be 29 ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd ( 1999) The Art, Science and Technology of Phannaceuticai Compounding).

As used herein, the term treatment and its cognâtes refer to improving AATD or its symptoms in a subject, delaying the onset of AATD or its symptoms in a subject, or lessening the severity of AATD or its symptoms in a subject. “Treatment” and its cognâtes as used herein, include, but are not limited to the following: improved liver and/or spleen function, lessened jaundice, improved lung function, lessened lung diseases and/or pulmonary exacerbations (e.g., emphysema), lessened skin disease (e.g., necrotizing panniculitis), increased growth in children, improved appetite, and reduced fatigue. Improvements in or lessening the severity of any of these symptoms can be readily assessed according to methods and techniques known in the art or subsequently developed.

The terms “about” and “approximately”, when used in connection with doses, amounts, or weight percent of ingrédients of a composition or a dosage form, include the value of a specified dose, amount, or weight percent or a range of the dose, amount, or weight percent that is recognized by one of ordinary ski 11 in the art to pro vide a phannacologîcal effect équivalent to that obtained from the specified dose, amount, or weight percent. In some embodiments, the term “about” reflects a variation of ± 10 % of a stated value. In some embodiments, the tenu “about” reflects a variation of ± 5 % of a stated value. In some embodiments, the term “about” reflects a variation of ± 2 % of a stated value.

Any one or more of the compounds of Formulae I, I-A, LB, I-C, LD, I-E, I-F, I-G, and I-H and tautomers of those compounds, pharmaceutically acceptable salts of those compounds and their tautomers, and deuterated dérivatives of any of the foregoing may be administered once daily, twice daily, or three times daily for the treatment of AATD. In spécifie embodiments, the any one or more compounds are selected from Compounds 1-342, tautomers of those compounds, pharmaceutically acceptable salts of those compounds and their tautomers, and deuterated dérivatives ot any of the foregoing. In some embodiments, at least one compound chosen from compounds of Formulae I, I-A, LB, Ι-C, LD, LE, LF, LG, and LH and tautomers of those compounds, pharmaceutically acceptable salts of those compounds and their tautomers, and deuterated dérivatives of any of the foregoing is administered once daily. In spécifie embodiments, a compound selected from Compounds 1-342, tautomers of those compounds, pharmaceutically acceptable salts of those compounds and their tautomers, and deuterated dérivatives of any of the foregoing is administered once daily. In some embodiments, at least one compound chosen from compounds of Formulae I, LA, LB, LC, LD, LE, LF, LG, and LH and tautomers of those compounds, pharmaceutically acceptable salts of those compounds and their tautomers, and deuterated dérivatives of any of the foregoing are administered twice daily.

In spécifie embodiments, a compound selected from Compounds 1-342, tautomers of those compounds, pharmaceutically acceptable salts of those compounds and their tautomers, and deuterated dérivatives of any of the foregoing is administered twice daily. In some embodiments, at least one compound chosen from compounds of Fonnulae I, I-A, I-B, I-C, I-D, I-E, I-F, I-G, and I-H and tautomers of those compounds, pharmaceutically acceptable salts of those compounds and their tautomers, and deuterated dérivatives of any of the foregoing are administered three times daily. In spécifie embodiments, a compound selected from Compounds 1-342, tautomers of those compounds, pharmaceutically acceptable salts of those compounds and their tautomers, and deuterated dérivatives of any of the foregoing is administered three times daily.

Any one or more of the compounds of Fonnulae I, I-A, I-B, I-C, I-D, I-E, I-F, I-G, and I-H and tautomers of those compounds, phannaceutically acceptable salts of those compounds and their tautomers, and deuterated dérivatives of any of the foregoing may be administered in combination with AAT augmentation therapy or AAT replacement therapy for the treatment of AATD. In spécifie embodiments, the any one or more compounds are selected from Compounds I-342, tautomers of those compounds, pharmaceutically acceptable salts of those compounds and their tautomers, and deuterated dérivatives of any of the foregoing.

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

In some embodiments, I0 mg to 1,500 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 a compound of Fonnulae 1, I-A, I-B, I-C, I-D, 1-E, I-F, I-G, and I-H and tautomers of those compounds, phannaceutically acceptable salts of those compounds and their tautomers, or deuterated dérivatives of such compound, tautomer, or sait are administered once daily, twice daily, or three times daily. In spécifie embodiments, 10 mg to 1,500 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, tautomers of those compounds, pharmaceutically acceptable salts of those compounds and their tautomers, or deuterated dérivatives of such compound, tautomer, or sait are administered once daily, twice daily, or three times daily.

One of ordinary skill in the art would recognize that, when an amount of a compound is disclosed, the relevant amount of a pharmaceutically acceptable sait form of the compound is an amount équivalent to the concentration of the free base of the compound. it is noted that the 31 disclosed amounts of the compounds, tautomers, pharmaceutically acceptable salts, and deuterated dérivatives are based upon the free base form of the reference compound. For example, “10 mg of at least one compound chosen from compounds of Formula (I) and pharmaceutically acceptable salts thereof’ includes 10 mg of a compound of Formula (I) and a concentration of a pharmaceutically acceptable sait of compounds of Formula (I) équivalent to 10 mg of compounds of Formula (I).

As used herein, the terms “crystalline form” and “Form” interchangeably refer to a crystal structure (or polymorph) having a particular molecular packîng arrangement in the crystal lattice. Crystalline forms can be identified and distinguished from each other by one or more characterization techniques including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, solid state nuclear magnetic résonance (SSNMR), differenfial scanning calorimetry (DSC), and/or thermogravimétrie analysis (TGA). Accordingly, as used herein, the ternis “crystalline Form [X] of Compound ([Y])” and “crystalline Form [C] of a [pharmaceutically acceptable] sait of Compound ([Y])” refer to unique crystalline forms that can be identified and distinguished from each other 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, the novel crystalline forms are characterized by an X-ray powder diffractogram having one or more signais at one or more specifîed two-theta values (° 2Θ).

As used herein, a crystalline form is “substantially pure” when it accounts for an amount by weight equal to or greater than 90% of the sum of ail solid form(s) of that compound in a sample as determined by a method in accordance with the art, such as quantitative ssNMR and/or XRPD. In some embodiments, the solid form is substantially pure when it accounts for an amount by weight equal to or greater than 95% of the sum of ail solid form(s) in a sample. In some embodiments, the solid form is substantially pure when it accounts for an amount by weight equal to or greater than 99% of the sum of ail solid fonn(s) in a sample.

As used herein, a compound is “substantially crystalline” when it accounts for an amount by weight equal to or greater than 70% of the sum of ail the solid forms of that compound in a sample as determined by a method in accordance with the art, such as quantitative ssNMR and/or XRPD. In some embodiments, the solid form is substantially crystalline when it accounts for an amount by weight equal to or greater than 75% of the sum of ail solid form(s) in a sample. In some embodiments, the solid form is substantially pure when it accounts for an amount by weight equal to or greater than 80% ofthe sum of ail solid form(s) in a sample. In some embodiments, the solid form is substantially pure when it accounts for an amount by weight equal to or greater than 85% of the sum of ail solid form(s) in a sample.

As used herein, the term “amorphous” refers to a solid materiai having no long range order in the position of its molécules. Amorphous solids are generally supercooled liquids in which the molécules are arranged in a random manner so that there is no welhdefmed arrangement, e.g., molecular packing, and no long range order. For example, an amorphous materiai is a solid materiai having no sharp characteristic signal(s) in its X-ray power diffractogram (i.e., is not crystalline as determined by XRPD). Instead, one or more broad peaks (e.g., halos) appear in its diffractogram. Broad peaks are characteristic of an amorphous solid. See, e.g., US 2004/0006237 for a comparison of diffractograms of an amorphous materiai and crystalline materiai. In addition, the widths of signais in ^,3C NMR and ^l9F NMR spectra of amorphous materiai are typically substantially broader than those in ^I3C NMR and ^l9F NMR spectra of crystalline materiai.

As used herein, a compound is “substantially amorphous” when it accounts for an amount by weight equal to or greater than 70% of the sum of ail the solid forms of that compound in a sample as determined by a method in accordance with the art, such as quantitative ssNMR and/or XRPD. In some embodiments, a compound that is substantially amorphous accounts for an amount by weight equal to or greater than 75% of the sum of ail the solid forms of that compound in a sample. In some embodiments, a compound that is substantially amorphous accounts for an amount by weight equal to or greater than 80% ofthe sum of ail the solid forms of that compound in a sample. In some embodiments, a compound that is substantially amorphous accounts for an amount by weight equal to or greater than 85% ofthe sum of ail the solid forms of that compound in a sample. In some embodiments, a compound that is substantially amorphous accounts for an amount by weight equal to or greater than 90% ofthe sum of ail the solid forms of that compound in a sample. In some embodiments, a compound that is substantially amorphous accounts for an amount by weight equal to or greater than 95% ofthe sum of ail the solid forms of that compound in a sample.

As used herein, a dispersion refers to a disperse System in which one substance, the dispersed phase, is distributed, in discrète units, throughout a second substance (the continuous phase or vehicle). The size ofthe dispersed phase can vary considerably (e.g. colloïdal particles of nanometer dimension, to multiple microns in size). In general, the dispersed phases can be solids, liquids, or gases. In the case of a solid dispersion, the dispersed and continuous phases are both solids. In phamaaceutical applications, a solid dispersion can include 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 the polymer constïtuting the dispersed phase, and the drug constîtutes the continous phase. In some embodiments, the dispersion includes amorphous Compound 33 or substantially amorphous Compound 33.

The tenu solid amorphous dispersion generally refers to a solid dispersion of two or more components, usually a drug and polymer, but possibly containing other components such as surfactants or other phannaceutical excipients, where Compound 33 is amorphous or substantially amorphous (e.g., substantially free of crystalline Compound 33), and the physical stability and/or dissolution and/or solubility of the amorphous drug is enhanced by the other components.

As used herein, the tenu “solvaté” refers to a crystal fonn comprising one or more molécules of a compound ofthe present disclosure and, incorporated into the crystal lattice, one or more molécules of a solvent or solvents in stoichiometric or nonstoichiometric amounts. When the solvent is water, the solvaté is referred to as a “hydrate”. The term “solvate/hydrate” refers to a crystal fonn comprising one or more molécules of a compound of the present disclosure and, incorporated into the crystal lattice, one or more molécules of a non-water solvent and 0-50% water in stoichiometric or nonstoichiometric amounts, such as 0-5%, 0-10%, 5-10%, 0-20%, 1020%, 10-15%, 15-20%, 5-20%, 0-25%, 20-25%, 10-25%, 15-25%, 5-25%, 0-30%, 5-30%, 1030%, 15-30%, 20-30%, 25-30%, 30-45%, 35-40%, 40-50%, and 45-50%.

As used herein, the term “XRPD” refers to X-Ray Power DiffractionXRPD patterns can be recorded at ambient conditions in transmission or reflection geometry using a diffractometer.

As used herein, the tenus “X-ray powder diffractogram,” “X-ray powder diffraction pattern,” “XRPD pattern” interchangeably refer to an experimental!y obtained pattern plotting signal positions (on the abscissa) versus signal intensifies on the ordinate). For an amorphous material, an X-ray powder diffractogram may include one or more broad signais; and for a crystalline material, an X-ray powder diffractogram may include one or more signais, each identified by its angular value as measured in degrees 2Θ (° 20), depicted on the abscissa of an X-ray powder diffractogram, which may be expressed as “a signal at ... degrees two-theta,” “a signal at [a] two-theta value(s)of ..and/or “a signal at at least... two-theta value(s) chosen from ....”

The term “X-ray powder diffractogram having a signal at ... two-theta values” as used herein refers to an XRPD pattern that contains X-ray reflection positions as measured and observed in X-ray powder diffraction experiments (° 20).

As used herein, an X-ray powder diffractogram is “substantially similar to that in [a particular] Figure” when at least 90%, such as at least 95%, ai least 98%, or at least 99%, ofthe signais in the two diffractograms overlap. In determining “substantiel sîmilarity,” one of ordinary skill in the art will understand that there may be variation in the intensities and/or signal positions în XRPD diffractograms even for the same crystalline fonn. Thus, those of ordinary 34 skill in the art will understand that the signal maximum values in XRPD diffractograms (in degrees two-theta (° 20) referred to herein) generally mean that value reported ±0.2 degrees 2Θ of the reported value, an art-recognized variance.

As used herein, the term “ambient conditions” means room température, open air condition and uncontrolled humidity condition.

A “signal” or “peak” as used herein refers to a point in the XRPD pattern where the intensity as measured in counts is at a local. One of ordinary skill in the art would recognize that one or more signais (or peaks) in an XRPD pattern may overlap and may, for example, not be apparent to the naked eye. Indeed, one of ordinary skill in the art would recognize that some artrecognized methods are capable of and suitable for determining whether a signal exists in a pattern, such as Rietveld refmement.

As used herein, “a signal at... degrees two-theta,” “a signal at [a] two-theta value[] of.. and/or “a signal at at least... two-theta value(s) chosen from ....” refer to X-ray reflection positions as measured and observed in X-ray powder diffraction experiments (° 2Θ).

The repeatability of the angular values is in the range of ± 0.2° 20, i.e., the angular value can be at the recited angular value + 0.2 degrees two-theta, the angular value - 0.2 degrees two-theta, or any value between those two end points (angular value ±0.2 degrees two-theta and angular value -0.2 degrees two-theta).

The terms “signal intensîties” and “peak intensifies” interchangeably refer to relative signal intensifies within a given X-ray powder diffractogram. Factors that can affect the relative signal or peak intensifies include sample thickness and preferred orientation (e.g., the crystalline particles are not distributed randomly).

As used herein, the term “SSNMR” refers to the analytical characterization method of solid State nuclear magnetic résonance. SSNMR spectra can be recorded at ambient conditions on any magnetically active isotope present in the sample. The typical examples of active isotopes for small molécule active pharmaceutical ingrédients include ^!H, ²H, ^l3C, ^l9F, ^3lP, ^l5N, ^l4N, ^î5Cl, ^UB, ⁷Li, ^l70,²³Na, ⁷⁹Br, and ^l95Pt.

As used herein, an SSNMR spectrum is “substantially similar to that in [a particular] Figure” when at least 90%, such as at least 95%, at least 98%, or at least 99%, ofthe signais in the two spectra overlap. In determining “substantial simîlarity,” one of ordinary skill in the ait will understand that there may be variation in the intensîties and/or signal positions in SSNMR spectra even for the same crystalline form. Thus, those of ordinary skill in the art will understand that the signal maximum values in SSNMR spectra (in ppm) referred to herein generally mean that value reported ±0.2 ppm of the reported value, an art-recognized variance.

As used herein, the term “DSC” refers to the analytical method of Differential Scanning Calorimetry.

As used herein, the term “TGA” refers to the analytical method of Thermo Gravimétrie (or thermogravimetric) Analysis.

II. Compounds and Compositions

In some embodiments, a compound ofthe invention is a compound of Fonnula I:

(O is chosen from (a) Ci-Cg linear, branched, and cyclic groups, wherein the CpCg linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the C|-Cs linear, branched, and cyclic groups are optionally substituted with 1-4 R^A; and (b) 5- to 14-meinbered aromatic rings optionally substituted with 1-4 R^A;

wherein each R^A is independently chosen from halogens, cyano, hydroxy, thiol, sulfonic acid, sulfonamîde, sulfinamide, amino, amide, carboxylic acid, 5- to 10membered aromatic rings, and Ci-Cô linear, branched, and cyclic groups, wherein the amide nitrogen atom in the amide of R^A is optionally substituted with a heterocyclyl group that is optionally further substituted with oxo, wherein the C]-C₆ linear, branched, and cyclic groups are chosen from alkyl, alkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, alkylsulfonamîde, alkylsulfinamide, aminoalkyl, and alkylamide, wherein the 5- to 10-membered aromatic rings and C|-C₆ linear, branched, and cyclic groups are optionally substituted with 1-4 substituents selected from halogens, Ci-Cô linear, branched, and cyclic groups, and methoxy, and wherein an R^A group is optionally linked to an R^B group on an R² group;

(ii) R* is chosen from (a) hydrogen, (b) Ci-Cg linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, cyanoalkyl, hydroxy, alkylsulfonyl, and

Ci-Cé linear, branched, and cyclic groups, wherein the Ci-C₆ linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the C_rC₆ linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and

Cj-Cè linear, branched, and cyclic alkoxy groups, (c) Cj-Cg linear, branched, and cyclic alkoxy or cyclic thioalkyl groups optionally substituted with 1-4 substituents independently chosen from halogens, cyano, cyanoalkyl, sulfone, sulfonamide, hydroxy, and

Ci-Côlinear, branched, and cyclic alkyl groups that are optionally substituted with 1 -4 halogens or alkoxy groups;

O |-S-R^C

Il (d) O groups, wherein R^c is chosen from:

(aa) hydroxy, (bb) C_rC₈ linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and

Cj-Cf, linear, branched, and cyclic groups, wherein the C1-C5 linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Ci-Cô linear, branched, and cyclic groups are optionally substituted with l -4 substituents independently chosen from halogens, hydroxy, and Ci-Cô linear, branched, and cyclic alkoxy groups, and (cc) Cj-Cg linear, branched, and cyclic alkoxy groups optionally substituted with 1 -4 substituents independently chosen from 10 halogens, cyano, hydroxy, and

Ci-Cô linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 halogens;

fs-N(R^D)₂ (e) O groups, wherein each R^D is independently chosen from (aa) hydrogen, (bb) Cj-Cg linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 substituents independently chosen from halogens, 20 cyano, hydroxy, and

Ci-Cô linear, branched, and cyclic groups, wherein the C|-C₆ linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Ci-C₆ linear, branched, and cyclic groups are optionally 25 substituted with 1-4 substituents independently chosen from halogens, hydroxy, and

Ci-Cô linear, branched, and cyclic alkoxy groups, and (cc) C]-Cg linear, branched, and cyclic alkoxy groups optionally substituted with 30 1 -4 substituents independently chosen from halogens, cyano, hydroxy, and

C|-C& linear, branched, and cyclic alkyl groups that are optionally substituted with 1 -4 halogens, or two R^d groups together with the nitrogen atom to which they are bonded may form a 4-8 membered ring, optionally comprising one or two heteroatoms in addition to the nitrogen to which they are attached, and which ring is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and Ci-Cf, linear, branched, and cyclic groups, wherein the C|-Cô linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Ci-Cô linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and Ci-Cf, linear, branched, and cyclic alkoxy groups; R^E

Ή

F E - (f) ^R groups, wherein R is chosen from:

(aa) hydrogen, (bb) CpCg linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and C|-Cô linear, branched, and cyclic groups, wherein the Cj-Cô linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the C|-Cô linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and Cj-Cô linear, branched, and cyclic alkoxy groups, (cc) C_rC₈ linear, branched, and cyclic alkoxy groups optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and Ci-Cé linear, branched, and cyclic alkyl groups that are optionally substituted with l-4 halogens;

(dd) 5- to 10-membered aromatic rings optionally substituted with I-4 R^A, and (ee) Ci-C₈ linear*, branched, and cyclic aminoalkyl groups, and R is chosen from:

(aa) hydroxy, (bb) C]-C₈ linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and

Ci-C₆ linear, branched, and cyclic groups, wherein the C|-C₆ linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Ci-Cô linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and

Ci-Cô linear, branched, and cyclic alkoxy groups, and (cc) C|-C₈ linear, branched, and cyclic alkoxy groups optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and

Ci-Cè linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 halogens;

O ^(CH₂)j-p-R^G (g) ^rG groups, wherein i is an integer ranging from 0 to 3 and each of R^G and R^G is independently chosen from (aa) hydroxy, (bb) C|-C_g linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and Cj-Cs linear, branched, and cyclic groups, wherein the Cj-Cê linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Ci-Cô linear, branched, and cyclic groups are optionally substituted with l-4 substituents independently chosen from halogens, hydroxy, and

Cj-Cô linear, branched, and cyclic alkoxy groups, and (cc) Ci-Cs linear, branched, and cyclic alkoxy groups optionally substituted with l-4 substituents independently chosen from halogens, cyano, hydroxy, and

Ci-Cs linear, branched, and cyclic alkyl groups that are optionally substituted with l-4 halogens, (dd) amino groups (ee) C_rCg linear, branched, and cyclic aminoalkyl groups, or R^g and R^G together with the phosphorous atom to which they are bonded may form a 4-8 membered ring, optionally comprising one or two heteroatoms in addition to the nitrogen to which they are attached, and which ring is optionally substituted with l-4 substituents independently chosen from halogens, cyano, hydroxy, and

C|-C₍, linear, branched, and cyclic groups, wherein the C|-C& linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Cj-Cô linear, branched, and cyclic groups are optionally substituted with l -4 substituents independently chosen from halogens, hydroxy, and

C_rCé linear, branched, and cyclic alkoxy groups; and (h) ^wherein each of R^H is independently chosen from (aa) C|-Cs linear, branched, and cyclic alkyi groups, wherein the alkyi group is optionally substituted with l-4 substituents independently chosen from halogens, cyano, hydroxy, and

Ci-Cf, linear, branched, and cyclic groups, wherein the Cj-Cs linear, branched, and cyclic groups are independently chosen from alkyi and alkoxy groups, and wherein the Ci-Cô linear, branched, and cyclic groups are optionally substituted with l-4 substituents independently chosen from halogens, hydroxy, and

C|-C6 linear, branched, and cyclic alkoxy groups, and (bb) Ci-Cs linear, branched, and cyclic alkoxy groups optionally substituted with l-4 substituents independently chosen from halogens, cyano, hydroxy, and

C|-Cé linear, branched, and cyclic alkyi groups that are optionally substituted with l -4 halogens;

(î) C|-Cô alkylamide;

(üi) R³ is chosen from 5- and 6-membered hetereocyclic rings (optionally substituted with oxo and/or Ci-Cô linear and branched alkyi groups) and 5- to 6-membered aromatic rings comprising 0-4 heteroatoms chosen from O, N, and S, wherein the 5-membered aromatic ring is optionally substituted with l-4 R^B groups and the 6-membered aromatic ring is optionally substituted with l-5 R^B groups, wherein the R^B groups are independently chosen from:

(a) amides, optionally substituted with l-3 groups selected from Cj-C₆ linear, branched, and cyclic alkyi groups (optionally substituted with heteroaryl), 4- to 6-membered heterocyclyl (optionally substituted with oxo, C_rC₆ linear, branched, and cyclic alkyi groups, hydroxyalkyl, amide, alkylsulfonyl, and acetamide); or wherein the amide nitrogen atom forms part of a 3- to 8-membered heterocyclyl ring (optionally substituted with alkylsulfonyl or Ci-Cô linear, branched, and cyclic alkyi groups), (b) imidazohdine-2,4-dione, (c) heterocyclyls optionally substituted with one more groups independently chosen from oxo, acyl, and Ci-C₆ linear, branched, and cyclic alkyi groups (which is optionally further substituted with l-3 groups independently chosen from oxo, hydroxy, and acyl), (d) phosphorous acid optionally esterified with a Ci-Cô linear, branched, or cyclic alkyl group, (e) di(Ci-C6)alkylphosphine oxides, (f) (Ci-Céjalkylphosphinic acids optionally esterified with a Ci-Cô linear, branched, or cyclic alkyl group, (g) halogens, (h)cyano, (i) hydroxy, (j) carboxylic acids optionally esterified with a uronic acid or a Cj-Cô linear, branched, or cyclic alkyl group, (k) oxo, (l) -B(OR^f)2 groups, wherein each R¹ is independently chosen from hydrogen and Ci-Cô linear, branched, and cyclic alkyl groups, or two OR¹ groups together with the boron atom to which they are bonded may form a 4-8 membered ring, optionally comprising one or two heteroatoms in addition to the nitrogen to which they are attached, and which ring is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and

Ci-Côlinear, branched, and cyclic groups, wherein the C_rC₆ linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Ci-Cô linear, branched, and cyclic groups are optionally substituted with 1 -4 substituents independently chosen from halogens, hydroxy, and

Cj-Cô linear, branched, and cyclic alkoxy groups, (m) 5- and 6-membered aromatic rings comprising 0-4 heteroatoms independently chosen from O, N, and S, optionally substituted with 1 or 2 substituents independently chosen from CiCô linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 substituents independently chosen from hydroxy, carboxylic acids, pyrrolîdin-2-one,

Ci-Cô linear, branched, and cyclic alkyl groups, and

C|-Cô linear, branched, and cyclic alkylsulfonyl groups, and

Cj-Cé linear, branched, and cyclic alkoxy groups, (n) sulfonic acid,

O

H-^rJ (ο) o groups, wherein R' is chosen from:

(aa) hydroxy, (bb) C|-Cg linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with l-4 substituents independently chosen from halogens, cyano, hydroxy, and

C|-Cô linear, branched, and cyclic groups, wherein the linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Ci-Cô linear, branched, and cyclic groups are optionally substituted with l-4 substituents independently chosen from halogens, hydroxy,

Ci-Cô linear, branched, and cyclic alkoxy groups, heterocyclyl optionally substituted with oxo, and amide (cc) C|-C_s linear, branched, and cyclic alkoxy groups optionally substituted with l -4 substituents independently chosen from halogens, cyano, hydroxy, and

C|-C& linear, branched, and cyclic alkyl groups that are optionally substituted with l-4 halogens (dd) 5- to 10-membered aromatîc rings optionally substituted with l-4 R^A, and (ee) Ci-C₈ linear, branched, and cyclic aminoalkyl groups,

O fs-N(R^K)₂ (p) ⁰ groups, wherein each R^K is independently chosen from:

(aa) hydrogen, (bb) C_rC₈ linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with l-4 substituents independently chosen from halogens, cyano, hydroxy, and Ci-Cè linear, branched, and cyclic groups, wherein the Cj-Cê linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Cj-Cg linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and Cj-Cô linear, branched, and cyclic alkoxy groups, and (cc) C]-Cg linear, branched, and cyclic alkoxy groups optionally substituted with

1-4 substituents independently chosen from halogens, cyano, hydroxy, and

Ci-Cé linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 halogens, or two R groups together with the nitrogen atom to which they are bonded may form a 4-8 membered ring, optionally comprising one or two heteroatoms in addition to the nitrogen to which they are attached, and which ring is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and

Ci-C₆ linear, branched, and cyclic groups, wherein the Ci-Cg linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the C|-C₆ linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and

Ci-C₆ linear, branched, and cyclic alkoxy groups

O (q) R groups, wherein each of R^L and R^L’ îs independently chosen from (aa) hydroxy, (bb) C|-Cg linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and C|-Cô linear, branched, and cyclic groups, wherein the Cj-Cô linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Ci-C^ linear, branched, and cyclic groups are optionally substituted with 1 -4 substituents independently chosen from halogens, hydroxy, and

C|-C₆ linear, branched, and cyclic alkoxy groups, and (cc) C_rC_g linear, branched, and cyclic alkoxy groups optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and C]-Cé linear, branched, and cyclic alkyl groups that are optionally substituted wiîh 1-4 halogens, (dd) amino groups (ee) Ci-C_s linear, branched, and cyclic aminoalkyl groups, or R^l and R^L together with the phosphorous atom to which they are bonded may form a 4-8 membered ring, optionally comprising one or two heteroatoms in addition to the nitrogen to which they are attached, and which ring is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and

Cj-Cô linear, branched, and cyclic groups, wherein the Ci-C₆ linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the C]-C₆ linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and

Ci-Cô linear, branched, and cyclic alkoxy groups, (r) C|-Cô linear, branched, and cyclic alkyl groups that are optionally substituted with l-4 substituents independently chosen from halogens, hydroxy, carboxylic acid,

Cj-Côlinear, branched, and cyclic alkoxy groups, heterocyclyl optionally substituted with oxo, and amide, (s) Ci-Cô linear, branched, and cyclic alkoxy groups that are optionally substituted with I-4 substituents independently chosen from halogens, hydroxy, carboxylic acid,

C]-Cô linear, branched, and cyclic alkyl groups, and

C|-C₆ linear, branched, and cyclic alkoxy groups, and

N'N . ÿ ^N

Λν (t) R^m groups, wherein R^M îs chosen from:

(aa) hydrogen, (bb) carboxylic acid, (cc) C_rC₈ linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and

Ci-C₆ linear, branched, and cyclic groups, wherein the C_rC₆ linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the C]-C₆ linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and

C]-C₆ linear, branched, and cyclic alkoxy groups, (dd) Ci-C₈ linear, branched, and cyclic alkoxy groups optionally substituted with 1 -4 substituents independently chosen from halogens, cyano, hydroxy, and

Cj-Cô linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 halogens (ee) 5- to 10-membered aromatic rings optionally substituted with 1-4 R^A (ff) halogens (gg) hydroxy (u) O-Rⁿ wherein R^N is chosen from (aa) Cj-Cg linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and

Ci-C₆ linear, branched, and cyclic groups, wherein the Ci-C₆ linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the C|-Cô linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and

Ci-Cé linear, branched, and cyclic alkoxy groups, and (bb) Ci-C₈ linear, branched, and cyclic alkoxy groups optionally substituted with 1 -4 substituents independently chosen from halogens, cyano, hydroxy, and

Ci-C₆ linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 halogens,

O (v) N(R )_{2 j} wherein each R° is independently chosen from hydrogen and a Cj-Cg linear, branched, and cyclic alkyl group, wherein the alkyl group is optionally substituted with 14 substituents independently chosen from alkylsulfonyl, alkylamide, halogens, cyano, hydroxy, and Ci-Cô linear, branched, and cyclic groups, wherein the Ci-Cô linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Ci-Cô linear, branched, and cyclic groups are optionally substituted with l-4 substituents independently chosen from halogens, hydroxy, and

Ci-Cô linear, branched, and cyclic alkoxy groups, or two R° groups together with the nitrogen atom to which they are bonded may form a 4-8 membered ring, optionally comprising one or two heteroatoms in addition to the nitrogen to which they are attached, and which ring is optionally substituted with l-4 substituents independently chosen from halogens, cyano, hydroxy, and

Ci-Cô linear, branched, and cyclic groups, wherein the Ci-Cô linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the C|-C₆ linear, branched, and cyclic groups are optionally substituted with l-4 substituents independently chosen from halogens, hydroxy, and

Ci-Cô linear, branched, and cyclic alkoxy groups, and

J (w) , wherein Yi is chosen from oxygen, N-R^p, and N R^p , wherein R^p is chosen from a C_rC₈ linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and

Ci-Cô linear, branched, and cyclic groups, wherein the C_l-C₆ linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Ci-C₆ linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and Cj-C₆ linear, branched, and cyclic alkoxy groups, wherein 2 adjacent hydrogens on the 5- or 6-membered aromatic ring can be replaced by attachments to a second 5- or 6-membered aromatic ring comprising 0-4 heteroatoms independently chosen from O, N, and S to form a bicyclic R² group that is optionally substituted with l-6 R^b groups;

(iv) X¹ and X² are independently chosen from hydrogen, halogens, cyano, hydroxy, Cj-Cô linear, branched, and cyclic groups wherein the C|-Cô linear, branched, and cyclic groups are independently chosen from alkyl, alkoxy, thioalkyl, and aminoalkyl groups, and wherein the CiCô linear, branched, and cyclic groups are optionally substituted by 1-4 independently chosen halogens;

(v) each of W¹ and W² is independently selected from C and N;

(vi) each---represents a single or double bond, provided that no more than one - is a double bond;

(vii) each R³ is independently chosen from hydrogen, halogens, cyano, Ci-C₆ linear, branched, and cyclic alkyl groups, and Cj-Cô linear, branched, and cyclic alkoxy groups, wherein the Ci-C₆ linear, branched, and cyclic alkyl groups and the Cj-Cô linear, branched, and cyclic alkoxy groups are optionally substituted with 1 -4 substituents independently chosen from halogens, hydroxy groups, and carboxylic acid;

(viii) n is an integer chosen from 0, 1,2, and 3; and (ix) Z¹, Z², and Z³ are independently chosen from carbon, boron, nitrogen, sulfur, and oxygen, wherein when Z¹, Z², and/or Z³ are carbon or nitrogen, the valences of carbon and nitrogen are completed with hydrogen atoms, halogen, C_rC₆ linear, branched, and cyclic alkyl groups, and C|-C₆ linear, branched, and cyclic alkoxy groups, wherein the Cj-Cô linear, branched, and cyclic alkyl groups and the C_rC₆ linear, branched, and cyclic alkoxy groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy groups, and carboxylic acid, and wherein when Z¹, Z², or Z³ is boron, the valence of boron is completed with a hydrogen atom or a hydroxy group.

In some embodiments, R° is chosen from heteroaryl rings.

In some embodiments, Rⁿ is phenyl.

In some embodiments, R° is unsubstituted.

In some embodiments, R° is substituted with 1-2 substituents.

In some embodiments, R° is substituted with l-2 substituents that are independently chosen from halogens, cyano, C1-C4 alkyl groups, and C1-C4 alkoxy groups.

In some embodiments, R° is substituted with l-2 substituents that are independently chosen from fluorine, chlorine, methyl, and methoxy.

In some embodiments, R¹ is chosen from Ci-Cô linear and branched alkyl groups and C3C₆ cyclic alkyl groups.

In some embodiments, R¹ is chosen from C3 branched alkyl groups and Cô cyclic alkyl groups.

In some embodiments, R¹ is chosen from C4-C6 cyclic alkyl groups wherein one carbon atom is replaced by a heteroatom.

In some embodiments, R¹ is chosen from CL cyclic alkyl groups wherein one carbon atom is replaced by a heteroatom.

In some embodiments, R¹ is chosen from C1-C4 linear and branched alkyl groups and C4C& cyclic alkyl groups, wherein an alkyl group is substituted with a methyl, ethyl, methoxy, isopropoxy, cyano, cyanoalkyl, alkylsulfonyl, and/or hydroxy substituent.

O , -H~^rC

In some embodiments, R is chosen from O groups, wherein R^c îs chosen from Ci-Cô linear, branched, and cyclic alkyl groups.

O fs-R^c

In some embodiments, R is chosen from O groups, wherein R^c is chosen from C|-C₆ linear, branched, and cyclic alkyl groups substituted with 1 or 2 substituents independently chosen from Ci-Cô linear alkyl groups.

O

-H-^rC

In some embodiments, R is chosen from O groups, wherein R^c is chosen from C_rC₆ linear alkyl groups.

O f-S-R^c ïn some embodiments, R¹ is chosen from O groups, wherein R^c is chosen from C_rC₆ linear alkyl groups substituted with 1 or 2 substituents independently chosen from C_rC₆ linear alkyl groups.

fs-N(R^D)₂

In some embodiments, R¹ is chosen from O groups, wherein each R^D is independently chosen from hydrogen and Cj-Cg linear, branched, and cyclic alkyl groups.

O ^S-N(R^d)₂

In some embodiments, R¹ is chosen from O groups, wherein each R^D is independently chosen from hydrogen and Ci-Cg linear, branched, and cyclic alkyl groups 5 substituted with 1 or 2 substituents independently chosen from Cj-Cô linear alkyl groups.

O fs-N(R°)₂

In some embodiments, R¹ is chosen from 0 groups, wherein cach R^D is independently chosen from hydrogen and Cj-Cg linear alkyl groups.

R^{e !}5ⁿ

In some embodiments, R¹ îs chosen from R^F groups, wherein R^E is chosen from hydrogen and C|-Cg linear, branched, and cyclic alkyl groups.

R^E

Ή ,O

0^<S'

In some embodiments, R¹ is chosen from R^F groups, wherein R^E is chosen from hydrogen and Cj-C_s linear, branched, and cyclic alkyl groups substituted with 1 or 2 substituents independently chosen from Cj-Cô linear alkyl groups.

_re

In some embodiments, R¹ is chosen from R^F groups, wherein R^E is chosen from hydrogen and C₍-Cg linear alkyl groups.

R^E

In some embodiments, R¹ is chosen from R^F groups, wherein R^F is chosen from hydroxy and Cj-Cg linear, branched, and cyclic alkyl groups.

R^E

Ή ,o

In some embodiments, R¹ is chosen from R^F groups, wherein R^E is chosen from hydroxy and C_rCg linear, branched, and cyclic alkyl groups substituted with 1 or 2 substituents independently chosen from Cj-Cô linear alkyl groups.

rE

In some embodiments, R¹ is chosen from ^rF groups, wherein R^F is chosen from hydroxy and C_rC₈ linear alkyl groups.

O ^(CH₂)_rP-R^G

In some embodiments, R¹ is chosen from R^G groups, wherein each of R^G and R^g is independently chosen from Ci-C₈ linear, branched, and cyclic alkyl groups.

^(CH^-P-R⁰

In some embodiments, R¹ is chosen from R^G groups, wherein each of R^G and R^g is independently chosen from Cj-C₈ linear, branched, and cyclic alkyl groups substituted with 1 or 2 substituents independently chosen from Ci-C₆ linear alkyl groups.

In some embodiments, R¹ is chosen from wherein each R^H is independently chosen from C|-C₈ linear, branched, and cyclic alkyl groups.

In some embodiments, R¹ is chosen from ^^S^^R >3 _wherein each R¹¹ is independently chosen from Ci-C₈ linear, branched, and cyclic alkyl groups substituted with I or 2 substituents independently chosen from Ci-C& linear alkyl groups.

In some embodiments, R¹ is chosen from ^“^S'(^R Î3 wherein each R^H is independently chosen from Cj-C_s linear alkyl groups.

In some embodiments, R¹ is chosen from hydrogen, methyl, trîm ethyl si lyl,

In some embodiments, R² is chosen from 5-membered aromatic rings comprising 0-4 heteroatoms chosen from O, N, and S, wherein the ring is optionally substituted with l-4 R^B groups. In some embodiments, R² îs chosen from 6-membered aromatic rings comprising 0-4 heteroatoms chosen from O, N, and S, wherein the ring is optionally substituted with 1-5 R^B groups.

In some embodiments, R is chosen from 5-membered aromatic rings comprising 1 or 2 nitrogen heteroatoms, wherein the ring is optionally substituted with 1-4 R^B groups. In some embodiments, R² is chosen from 6-membered aromatic rings comprising 1 or 2 nitrogen heteroatoms, wherein the ring is optionally substituted with 1-5 R^B groups.

In some embodiments, R groups are independent chosen from halogens, cyano, hydroxy, carboxylic acid, Ci-C₆ linear, branched, and cyclic alkyl groups, and CpCe linear, branched, and cyclic alkoxy groups.

In some embodiments, R^B groups are independent chosen from halogens, hydroxy, carboxylic acid, C|-C₆ linear alkyl groups, and C|-C₆ linear alkoxy groups.

In some embodiments, R^B groups are independent chosen from fluorine, chlorine, methyl, methoxy, hydroxy, and carboxylic acid.

In some embodiments, Z¹, Z², and Z³ are independently chosen from carbon, nitrogen, sulfur, and oxygen.

In some embodiments, when Z¹, Z², and/or Z³ are carbon or nitrogen, the valences of carbon and nitrogen are completed with hydrogen atoms.

In some embodiments, Z¹, Z², or Z³ is boron, and the valence of boron is completed with a hydrogen atom or a hydroxy group.

In some embodiments, at least one of Z¹, Z², and Z³ is nitrogen. In some embodiments, two of Z¹, Z², and Z³ are nitrogen and the other is chosen from carbon and nitrogen.

In some embodiments, each R³ is independently chosen from hydrogen, C|-C& linear alkyl groups, and heterocyclyl groups.

In some embodiments, X¹ and X² are independently chosen from hydrogen and halogen.

In some embodiments, X¹ and X² are each hydrogen.

In some embodiments, the compound of the invention is a compound of any one of

Formulae I-A, I-B, I-C, I-D, I-E, I-F, I-G, and I-H

l-A l-B l-C

l-D |-E |-F

l-H a tautomer thereof, a phannaceutically acceptable salts of such compound or tautomer, or a deuterated dérivative of any of the foregoing, wherein:

R , R , R\ R , and n are defined for compounds of Formula (I)

X¹ and X² are independently chosen from hydrogen and fluorine, or X¹ is fluorine and X² is hydrogen, or X² îs fluorine and X¹ is hydrogen, or X¹ and X² are each hydrogen, each of W¹ and W² is independently selected from C and N,

Y¹, Y², Y³, and Y⁴ are independently chosen from hydrogen, cyano, halogen groups,

C_rC₆ linear, branched, and cyclic alkyl groups,

Ci-Cô linear, branched, and cyclic alkoxy groups that are optionally substituted with 1-4 substituents independently chosen from hydroxy,

Ci-Cô linear, branched, and cyclic alkyl groups, and

Ci-C(, linear, branched, and cyclic alkoxy groups;

Y ⁵, Y⁶, Y⁷, and Y⁸ are independently chosen from hydrogen, halogen groups hydroxy,

Ci-C₆ linear, branched, and cyclic alkyl groups optionally substituted with 1-4 independently chosen halogen substituents, and

Ci-Cô linear, branched, and cyclic alkoxy groups,

Y ⁹, Y¹⁰, Y¹¹, Y¹², Y¹³, Y¹⁴, Y¹⁵, and Y¹⁶ are independently chosen from carboxylic acid, hydrogen, halogen groups,

C|-Cô linear, branched, and cyclic alkylsulfonyl groups,

Ci-C₆ linear, branched, and cyclic alkyl groups optionally substituted with 1-4 independently chosen halogen substituents, and

Ci-C₆ linear, branched, and cyclic alkoxy groups,

Y ¹⁷, Y¹⁸, Y¹⁹, Y²⁰, and Y²¹ are independently chosen from hydrogen, carboxylic acid, halogen groups, cyano, hydroxy,

Cj-Q linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and carboxylic acid,

Ci-C₆ linear, branched, and cyclic alkoxy groups that are optionally substituted with a carboxylic acid group, dihydroxyboryl, sulfonic acid, carboxylic acid optionally esterified with a uronic acid, tetrazolyl groups, aminosulfonyl groups, optionally substituted with 1 or 2 substituents independently chosen from

Ci-Cô linear, branched, and cyclic alkyl groups, and

Ci-Cô linear, branched, and cyclic alkylsuifonyl groups with the proviso that, in Formula I-E, at least one of Y¹⁷, Y¹⁸, Y¹⁹, Y²⁰, and Y²¹ is hydrogen.

In some embodiments, in a compound of any one of Fonnulae I-A, I-B, I-C, I-D, I-E, I-F, I-G, and I-H, one or more of Y¹⁷, Y¹⁸, Y¹⁹, Y^2fl, and Y²¹ is chosen from methyl, methoxy, cyano,

-K^0H fluorine, hydroxy, -CFj, -B(OH)2, -SO₂NHMe, ~SO₂Me, -SO₂H, -CH₂CO₂H, ^CFs,

In some embodiments, a compound of the invention is a compound of Formula I':

wherein:

(i) R⁰' is chosen from (a) Cj-Cg linear, branched, and cyclic groups, wherein the C_rC_g linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the C_rC_g linear, branched, and cyclic groups are optionally substituted with 1-4 R^A'; and (b) 5- to 14-membered aromatic rings optionally substituted with 1-4 R^A', wherein each R^A' is independently chosen from halogens, cyano, hydroxy, thiol, sulfonic acid, sulfonamide, sulfmamide, amino, amide, 5- to 10-membered aromatic rings, and CpCô linear, branched, and cyclic groups, wherein the Ci-C₆ linear, branched, and cyclic groups are chosen from alkyl, alkoxy, thioalkyl, alkylsulfoxide, alkylsuifonyl, alkylsulfonamide, alkylsulfinamide, aminoalkyl, and alkylamide, and wherein the 5- to

10-membered aromatic rings and Ci-Cô linear, branched, and cyclic groups arc optionally substituted with 1-4 substituents selected from halogens and methoxy, and wherein an R^A' group is optionally linked to an R¹⁸' group on an R²' group;

(ii) R¹ ' is chosen from (a) hydrogen, (b) Cj-Cg linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1 -4 substituents independently chosen from halogens, cyano, hydroxy, and

Cj-C₆ linear, branched, and cyclic groups, wherein the Cj-Cô linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Cj-C& linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and Cj-Cô linear, branched, and cyclic alkoxy groups, and (c) Cj-Cg linear, branched, and cyclic alkoxy or cyclic thioalkyl groups optionally substituted with 1-4 substituents independently chosen from halogens, cyano, sulfone, sulfonamide, hydroxy, and

Cj-Cô linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 halogens;

O

H —s- R^c

II (d) O groups, wherein R^c' is chosen from:

(aa) hydroxy, (bb) Cj-Cg linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and

Cj-Cô linear, branched, and cyclic groups, wherein the C|-Cô linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Ci-C& linear, branched, and cyclic groups are optionally substituted with l -4 substituents independently chosen from halogens, hydroxy, and

Ci-Cô linear, branched, and cyclic alkoxy groups, and (cc) Ci-Cg linear, branched, and cyclic alkoxy groups optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and C|-Cô linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 halogens;

O

-^-S-N(R^d')₂ (e) O groups, wherein each R^D is independently chosen from (aa) hydrogen, (bb) Cj-Cg linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and

Ci-Cô linear, branched, and cyclic groups, wherein the Ci-Cô linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Ci-Cô linear, branched, and cyclic groups are optionally substituted with 1 -4 substituents independently chosen from halogens, hydroxy, and

Ci-Cô linear, branched, and cyclic alkoxy groups, and (cc) Ci-C₈ linear, branched, and cyclic alkoxy groups optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and

C|-Cé linear, branched, and cyclic alkyi groups that are optionally substituted with l-4 halogens, or two R^d groups together with the nitrogen atom to which they are bonded may form a 4-8 membered ring, optionally comprising one or two heteroatoms in addition to the nitrogen to which they are attached, and which ring is optionally substituted with l-4 substituents independently chosen from halogens, cyano, hydroxy, and

Ci-Cô linear, branched, and cyclic groups, wherein the Ci-Cô linear, branched, and cyclic groups are independently chosen from alkyi and alkoxy groups, and wherein the Cj-Cô linear, branched, and cyclic groups are optionally substituted with l-4 substituents independently chosen from halogens, hydroxy, and

C|-C₆linear, branched, and cyclic alkoxy groups;

R^Ê'

Ή ,o

O<3 (f) r^f groups, wherein R^E is chosen from:

(aa) hydrogen, (bb) C|-C₈ linear, branched, and cyclic alkyi groups, wherein the alkyi group is optionally substituted with l-4 substituents independently chosen from halogens, cyano, hydroxy, and

Ci-Cô linear, branched, and cyclic groups, wherein the C]-C₆ linear, branched, and cyclic groups are independently chosen from alkyi and alkoxy groups, and wherein the Ci-Q linear, branched, and cyclic groups are optionally substituted with l-4 substituents independently chosen from halogens, hydroxy, and

Ci-Cô linear, branched, and cyclic alkoxy groups, (cc) Ci-C_g linear, branched, and cyclic alkoxy groups optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and Ci-Cô linear, branched, and cyclic alkyl groups thaï are optionally substituted with l-4 halogens;

(dd) 5- ίο l O-membered aromatic rings optionally substituted with l-4 R^A, and (ee) CpC₈ linear, branched, and cyclic amînoalkyl groups, and R is chosen from:

(aa) hydroxy, (bb) Ci-C₈ linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and

Cj-C₆ linear, branched, and cyclic groups, wherein the Ci-C₆ linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Ci-Cf, linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and

Ci-Cû linear, branched, and cyclic alkoxy groups, and (ce) C|-C₈ linear, branched, and cyclic alkoxy groups optionally substituted with 1 -4 substituents independently chosen from halogens, cyano, hydroxy, and C|-Cô linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 halogens;

O ^(CH^-p-R⁶ (g) ^rG groups, wherein i^r is an integer ranging from 0 to 3 and each of

G G

R and R îs independently chosen from (aa) hydroxy, (bb) Cj-C₈ linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1 -4 substituents independently chosen from halogens, cyano, hydroxy, and

Ci-Q linear, branched, and cyclic groups, wherein the C|-Cô linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Ci-Ce linear, branched, and cyclic groups are optionally substituted with l-4 substituents independently chosen from halogens, hydroxy, and

C;-Cô linear, branched, and cyclic alkoxy groups, and (cc) C_rC₈ linear, branched, and cyclic alkoxy groups optionally substituted with l -4 substituents independently chosen from halogens, cyano, hydroxy, and

Cj-Cô linear, branched, and cyclic alkyl groups that are optionally substituted with l-4 halogens, (dd) amino groups (ee) C_rC₈ linear, branched, and cyclic aminoalkyl groups, or R and R together with the phosphorous atom to which they are bonded may form a 4-8 membered ring, optionally comprising one or two heteroatoms in addition to the nitrogen to which they are attached, and which ring is optionally substituted with l-4 substituents independently chosen from halogens, cyano, hydroxy, and

C|-C₆ linear, branched, and cyclic groups, wherein the C_rC₆ linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Cj-Cô linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and

C|-C₆ linear, branched, and cyclic alkoxy groups; and (h) * ' ⁷³ wherein each of R^M îs independently chosen from (aa) Ci-C₈ linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and

Cj-C₆ linear, branched, and cyclic groups, wherein the Cj-C₆ linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Ci-C^ linear, branched, and cyclic groups are optionally substituted with 1 -4 substituents independently chosen from halogens, hydroxy, and

Cj-Cf, linear, branched, and cyclic alkoxy groups, and (bb) Ci-C₈ linear, branched, and cyclic alkoxy groups optionally substituted with 1 -4 substituents independently chosen from halogens, cyano, hydroxy, and

Ci-C₆ linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 halogens;

(iii) R² is chosen from 5- and 6-membered aromatic rings comprising 0-4 heteroatoms chosen from O, N, and S, wherein the 5-membered ring is optionally substituted with 1-4 R^B groups and the 6-membered ring is optionally substituted with 1-5 R^B groups, wherein the R^B groups are independently chosen from (a) optionally substituted amides, (b) imidazolidine-2,4-dione, (c) optionally substituted heterocyclyls, (d) phosphorous acid optionally esterified with a C]-C& linear, branched, or cyclic alkyl group, (e) di(C|-C6)alkylphosphine oxides, (0 (Ci-C^alkylphosphinic acids optionally esterified with a Cj-Cg linear, branched, or cyclic alkyl group, (g) halogens, (h) cyano, (i) hydroxy, (j) carboxylic acid optionally esterified with a uronic acid or a C|-C₆ linear, branched, or cyclic alkyl group, (k) oxo, (!) -B(OR¹ )₂ groups, wherein each R¹ is independently chosen from hydrogen and Cj-Cô linear, branched, and cyclic alkyl groups, or two OR¹ groups together with the boron atom to which they are bonded may form a 4-8 membered ring, optionally comprising one or two heteroatoms in addition to the nitrogen to which they are attached, and which ring is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and

Cj-Cô linear, branched, and cyclic groups, wherein the Cj-Cô linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the C|-C₆ linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and

Cj-Cg linear, branched, and cyclic alkoxy groups, (m) 5- and 6-membered aromatic rings comprising 0-4 heteroatoms independently chosen from O, N, and S, optionally substituted with 1 or 2 substituents independently chosen from C|C₆ linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 substituents independently chosen from hydroxy, carboxylic acids, pyrrolidin-2-one,

C|-C₆ linear, branched, and cyclic alkyl groups, and

Cj-Cô linear, branched, and cyclic alkylsulfonyl groups, and Cj-Cô linear, branched, and cyclic alkoxy groups, (n) sulfonic acid,

O s ¹¹ „ ¹¹ (ο) o groups, wherein R^J is chosen froin:

(aa) hydroxy, (bb) C|-C₈ linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1 -4 substituents independently chosen from halogens, cyano, hydroxy, and Ci-Cô hnear, branched, and cyclic groups, wherein the Ci-Cô linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the C|-Cô linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and

C|-Cô linear, branched, and cyclic alkoxy groups, and (cc) C_rC₈ linear, branched, and cyclic alkoxy groups optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and

Ci-Cô linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 halogens (dd) 5- to 10-membered aromatic rings optionally substituted with 1-4 R^A, and (ee) Ci-C₈ linear, branched, and cyclic aminoalky] groups,

O ^-S-N(R^k)₂ (p) ⁰ groups, wherein each R^K is independently chosen from:

(aa) hydrogen, (bb) C_rC₈ linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and

Ci-Cô linear, branched, and cyclic groups, wherein the Ci-C₆ linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Ci-Cô linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and

C₍-Cô linear, branched, and cyclic alkoxy groups, and (cc) C]-C₈ linear, branched, and cyclic alkoxy groups optionally substituted with l-4 substituents independently chosen from halogens, cyano, hydroxy, and

C]-C₆ linear, branched, and cyclic alkyl groups that are optionally substituted with l -4 halogens, or two R groups together with the nitrogen atom to which they are bonded may form a 4-8 membered ring, optionally comprising one or two heteroatoms in addition to the nitrogen to which they are attached, and which ring is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and

Ci-C₆linear, branched, and cyclic groups, wherein the C_rC₆ linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the C_rC₆ linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and

Cj-C₆ linear, branched, and cyclic alkoxy groups

O

-|-P-R^L (q) ^rL groups, wherein each of R^L and R^L ' is independently chosen from (aa) hydroxy, (bb) C_rC₈ linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and

C]-C₆ linear, branched, and cyclic groups, wherein the Cj-Cô linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Ci-Ce linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and

Ci-Cô linear, branched, and cyclic alkoxy groups, and (cc) Ci-Cg linear, branched, and cyclic alkoxy groups optionally substituted with l-4 substituents independently chosen from halogens, cyano, hydroxy, and

C]-Cf, linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 halogens, (dd) amîno groups (ee) Ci-Cg linear, branched, and cyclic aminoalkyl groups, or R^l and R^L together with the phosphorous atom to which they are bonded may form a 4-8 membered ring, optionally comprising one or two heteroatoms in addition to the nitrogen to which they are attached, and which ring is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and

C|-C₆ linear, branched, and cyclic groups, wherein the C|-C₆ linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Cj-Cô linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and

Ci-C₆ linear, branched, and cyclic alkoxy groups, (r) Ci-C₆ linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, carboxylic acid, and

Cj-C₆ linear, branched, and cyclic alkoxy groups, (s) Ci-Cs linear, branched, and cyclic alkoxy groups that are optionally substituted with 1 -4 substituents independently chosen from halogens, hydroxy, 67 carboxylic acid,

Ci-Cô linear, branched, and cyclic alkyl groups, and

Cj-C₆ linear, branched, and cyclic alkoxy groups, and

N'N

Jl N (t) ^rM groups, wherein R^M is chosen from:

(aa) hydrogen, (bb) carboxylic acid, (cc) C]-Cg linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with I-4 substituents independently chosen from halogens, cyano, hydroxy, and

C_rC₆ linear, branched, and cyclic groups, wherein the Cj-C₆ linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the C_rC₆ linear, branched, and cyclic groups are optionally substituted with I -4 substituents independently chosen from halogens, hydroxy, and

C;-Câ linear, branched, and cyclic alkoxy groups, (dd) Cj-Cg linear, branched, and cyclic alkoxy groups optionally substituted with l -4 substituents independently chosen from halogens, cyano, hydroxy, and

CrQ, linear, branched, and cyclic alkyl groups that are optionally substituted with l-4 halogens (ee) 5- to 10-membered aromatic rings optionally substituted with l-4 R^A (u) O-Rⁿ wherein R^N is chosen from (aa) C_rC₈ linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with l-4 substituents independently chosen from halogens, cyano, hydroxy, and

C1-C& linear, branched, and cyclic groups, wherein the C|-C& linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the C_t-C₆ linear, branched, and cyclic groups are optionally substituted with l-4 substituents independently chosen from halogens, hydroxy, and

Ci-Cô linear, branched, and cyclic alkoxy groups, and (bb) Ci-C₈ linear, branched, and cyclic alkoxy groups optionally substituted with l-4 substituents independently chosen from halogens, cyano, hydroxy, and Ci-Cê linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 halogens,

O o· (v) ^N(^R >2 _; wherein each R° is independently chosen from hydrogen and a Ci-C₈ linear, branched, and cyclic alkyl group, wherein the alkyl group is optionally substituted with 14 substituents independently chosen from alkylsulfonyl, alkylamide, halogens, cyano, hydroxy, and

Ci-C₆ linear, branched, and cyclic groups, wherein the C|-C₆ linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Ci-C₆ linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and

Ci-C& linear, branched, and cyclic alkoxy groups, or two R° groups together with the nitrogen atom to which they are bonded may form a 4-8 membered ring, optionally comprising one or two heteroatoms in addition to the nitrogen to which they are attached, and which ring is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and Ci-C₆linear, branched, and cyclic groups, wherein the Ci-Cô linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the C|-Cô linear, branched, and cyclic groups are optionally substituted with l-4 substituents independently chosen from halogens, hydroxy, and

Cj-Cô linear, branched, and cyclic alkoxy groups, and

(w) T , wherein Vf is chosen from oxygen, N-R^p , and N R^p , wherein R^P is chosen from a C|-Cg linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with l-4 substituents independently chosen from halogens, cyano, hydroxy, and

Cj-Cô linear, branched, and cyclic groups, wherein the Ci-Cô linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Ci-Cô linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and Cj-Cô linear, branched, and cyclic alkoxy groups, wherein 2 adjacent hydrogens on the 5- or 6-membered aromatic ring can be replaced by attachments to a second 5- or 6-membered aromatic ring comprising 0-4 heteroatoms independently chosen from O, N, and S to form a bicyclic R² group that is optionally substituted with 1-6 R groups;

(iv) X¹ and X² are independently chosen from hydrogen, halogens, cyano, hydroxy, Cj-Cô linear, branched, and cyclic groups wherein the Cj-Cô linear, branched, and cyclic groups are independently chosen from alkyl, alkoxy, thioalkyl, and aminoalkyl groups, and wherein the CjCô linear, branched, and cyclic groups are optionally substituted by 1-4 independently chosen halogens;

(v) each - - - represents a single or double bond, provided that no more than one === is a double bond;

(vi) each R³ is independently chosen from hydrogen, halogens, cyano, Cj-Cô linear, branched, and cyclic alkyl groups, and Cj-Cô linear, branched, and cyclic alkoxy groups, wherein 5 the linear, branched, and cyclic alkyl and alkoxy groups are optionally substituted with l-4 independently chosen halogens;

(vîî) n- is an integer chosen from 0, 1,2, and 3; and (viii) Z , Z , and Z are independently chosen from carbon, boron, nitrogen, sulfur, and oxygen, wherein when Z¹ , Z² , and/or Z³ are carbon or nitrogen, the valences of carbon and nitrogen are completed with hydrogen atoms, and wherein when Z¹, Z² , or Z³ is boron, the valence of boron is completed with a hydrogen atom or a hydroxy group.

In some embodiments, the compound of the invention is selected from Compounds 1-342 depicted in Table 1. A wavy line in a compound in Table 1 (i.e., ) depicts a bond between two atoms and indicates a position of mixed stereochemistry for a collection of molécules, such as a racemic mixture, cis/trans isomers, or (E)/(Z) isomers. An asterisk adjacent to an atom (e.g., in a compound in Table 1, indicates a stereogenic center of an unassigned, single stereoisomer in the molécule.

Table 1. Compounds 1-342

SI

ιοο

ΙΟΙ

102

103

104

105

106

107

108

Sonie embodiments of the invention include dérivatives of Compounds 1-342 or compounds of Formulae I, I-A, I-B, I-C, l-D, I-E, I-F, I-G, and LH. In some embodiments, the dérivatives are Silicon dérivatives in which at least one carbon atom in a compound selected from 5 Compounds 1-342 or compounds of Formulae I, LA, LB, LC, LD, LE, LF, LG, and LH has been replaced by Silicon. In some embodiments, the dérivatives are boron dérivatives, in which at least one carbon atom in a compound selected from Compounds 1-342 or compounds of Formulae I, LA, LB, LC, LD, LE, LF, LG, and LH lias been replaced by boron. In other embodiments, the dérivatives are phosphate dérivatives, in which at least one carbon atom in a 10 compound selected from Compounds 1-342 or compounds of Formulae I, LA, LB, LC, I-D, LE,

LF, I-G, and I-H has been replaced by phosphorus. Because the general properties of Silicon, boron, and phosphores are similar to those of carbon, replacement of carbon by Silicon, boron, or phosphorus can resuit in compounds with similar biological activity to a carbon containing original compound.

In some embodiments, the derîvative is a Silicon dérivative in which one carbon atom in a compound selected from Compounds 1-342 or compounds of Formulae I, LA, LB, LC, LD, LE, LF, I-G, and LH has been replaced by Silicon. In other embodiments, two carbon atoms hâve

109 been replaced b y Silicon. The carbon replaced by Silicon may be a non-aromatic carbon. In some embodiments a quatemary carbon atom of a tert-butyl moiety may be replaced by Silicon. In certain embodiments, the Silicon derivatives of the invention may include one or more hydrogen atoms replaced by deuterium. For ex ample, one or more hydrogens of a tert-butyl moiety in which the carbon has been replaced by Silicon, may be replaced by deuterium. In other embodiments, a Silicon derivatîve of a compound selected from Compounds 1-342 or compounds of Formulas I, I-A, l-B, I-C, I-D, I-E, I-F, I-G, and I-H may hâve Silicon incorporated înto a heterocycle ring.

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) solvaté Form A. In some embodiments, Compound 33 is in the fonn of Compound 33 hydrate Form A. In some embodiments, Compound 33 îs in the form of Compound 33 methanol (MeOH)/H₂O solvaté Fonn A. In some embodiments, Compound 33 is in the fonn of Compound 33 Form C. In some embodiments, Compound 33 is in the fonn 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 fonn of Compound 33 Fonn G. In some embodiments, Compound 33 is in the form of Compound 33 Fonn H. In some embodiments, Compound 33 is în the form of Compound 33 Fonn I. In some embodiments, Compound 33 is in the fonn of Compound 33 tetrahydrofuran (THF) solvaté Form A. In some embodiments, Compound 33 is in the fonn of

Compound 33 Fonn J. In some embodiments, Compound 33 îs în the fonn of Compound 33

Form K. In some embodiments, Compound 33 is in the form of Compound 33 Fonn L. In some embodiments, Compound 33 is in the form of Compound 33 2-methyltetrahydrofuran (Me-THF) solvaté Fonn A. In some embodiments, Compound 33 is in the fonn of Compound 33 Form M.

In some embodiments, Compound 33 is in the fonn of Compound 33 Form N. In some embodiments, Compound 33 is in the form of Compound 33 Fonn O. In some embodiments,

Compound 33 is in the form of Compound 33 potassium sait Form A. In some embodiments,

Compound 33 is in the fonn of Compound 33 potassium sait Form B. In some embodiments,

Compound 33 is in the form of Compound 33 potassium sait Fonn C. In some embodiments,

Compound 33 is a mixture of any two or more of the foregoing.

1. Compound 33 Form A

110

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

Thus, in some embodiments, Compound 33 Fonn A is substantially crystalline. In some embodiments, Compound 33 Fonn A is substantially pure crystalline. In some embodiments, Compound 33 Form A is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation. FIG. IA provides an Xray powder diffractogram of Compound 33 Form A at room temperature.

In some embodiments, Compound 33 Form A is characterized by an X-ray powder diffractogram having signais at one or more of 15.5 ± 0.2 degrees two-theta, 17.5 ± 0.2 degrees two-theta, 19.2 ± 0.2 degrees two-theta, and 19.5 ± 0.2 degrees two-theta,. In some embodiments, Compound 33 Form A is characterized by an X-ray powder diffractogram having signais at 15.5 ± 0.2 degrees two-theta, 17.5 ± 0.2 degrees two-theta, 19.2 ± 0.2 degrees twotheta, and 19.5 ± 0.2 degrees two-theta,. In some embodiments, Compound 33 Fonn A is characterized by an X-ray powder diffractogram having (a) signais at 19.2 ± 0.2 degrees twotheta, 19.5 ± 0.2 degrees two-theta, 15.5 ± 0.2 degrees two-theta, and 17.5 ± 0.2 degrees twotheta; and (b) at least one, at least two, at least three, at least four, or at least five signais selected from 11.0 ± 0.2 degrees two-theta, 14.2 ± 0.2 degrees two-theta, 16.0 ± 0.2 degrees two-theta, 16.2 ± 0.2 degrees two-theta, 20.9 ± 0.2 degrees two-theta, 21.3 ± 0.2 degrees two-theta, 21.8 ± 0.2 degrees two-theta, and 25.5 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Form A is characterized by an X-ray powder diffractogram having signais at 11.0 ± 0.2 degrees 111 two-theta, 14.2 ± 0.2 degrees two-theta, 15.5 ± 0,2 degrees two-theta, 16.0 ± 0.2 degrees twotheta, 16.2 ± 0.2 degrees two-theta, 17.5 ± 0.2 degrees two-theta, 19.2 ± 0.2 degrees two-theta, 19.5 ± 0.2 degrees two-theta, 20.9 ± 0.2 degrees two-theta, 21.3 ± 0.2 degrees two-theta, 21.8 ± 0.2 degrees two-theta, and 25.5 ± 0.2 degrees two-theta.

In some embodiments Compound 33 Form A is characterized b y an X-ray powder diffractogram substantially similar to FIG. IA.

In some embodiments, Compound 33 Fonn A is characterized as having a ^l3C ssNMR spectrum with 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. In some embodiments, Compound I sodium sait hydrate Form A îs characterized as having a ^l3C ssNMR spectrum with 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. In some embodiments, Compound 33 Form A is characterized as having a ¹³C ssNMR spectrum with 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. In some embodiments, Compound 33 Fonn A is characterized as having a ^l3C 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. In some embodiments, Compound 33 Form A is characterized as having a ^l3C 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 ppin. In some embodiments, Compound 33 Form A is characterized as having a ⁱ³C ssNMR spectrum with 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. In some embodiments, Compound 33 Form A is characterized as having a ^l3C 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. In some embodiments, Compound 33 Fonn A is characterized by a ^l3C ssNMR spectrum substantially similar to FIG. IB.

In some embodiments, Compound 33 Fonn A is characterized as having a ^l9F ssNMR spectrum with a peak at -109.3 ± 0.2 ppm. In some embodiments, Compound 33 Form A is characterized by a ^I9F ssNMR spectrum substantially similar to FIG. IC.

Another aspect ofthe invention provides a composition comprising Compound 33 Form A. In some embodiments, the composition of the invention comprises substantially pure 112 crystalline Compound 33 Form A. ïn some embodiments, the composition consista essentially of Compound 33 Form A.

Another aspect of the invention provides a method of making Compound 33 Form A. In some embodiments, Compound 33, Form A is prepared by:

(a) contactingmethyl 4-(5-(4-fluorophenyl)-l-pivaIoyl-6-(tetrahydro-2H-pyran-4-yl)-l,5dihydropyrrolo[2,3-f]indazol-7-yl)benzoate with a first organic solvent and a first base to fonn a first reaction mixture;

(b) adding water and a first acid to the first reaction mixture;

(c) isolating an organic portion from step (b), adding an alcohol and optionally adding water to the organic portion, and concentrating the mixture by distillation; and (d) isolating the compound 4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-l7/-pyrrolo[2,3f]indazol-7-yl]benzoic acid from the mixture from step (c) and drying the material to remove ail water content.

2. Compound 33 Form B

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

Thus, in some embodiments, Compound 33 Form B is substantially crystalline. In some embodiments, Compound 33 Form B îs substantially pure crystalline. In some embodiments, Compound 33 Form B is characterized by an X-ray powder diffractogram generated by an X-ray

113 powder diffraction analysis with an incident beam of Cu Ka radiation. FIG. 2A provides an Xray powder diffractogram of Compound 33 Form B at room température.

In some embodiments, Compound 33 Form B is characterized by an X-ray powder diffractogram having signais at one or more of 20.2 ± 0.2 degrees two-theta, 9.2 ± 0.2 degrees two-theta, 4.5 ± 0.2 degrees two-theta, and 15.1 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Form B is characterized by an X-ray powder diffractogram having signais at 20.2 ± 0.2 degrees two-theta, 9.2 ± 0.2 degrees two-theta, 4.5 ± 0.2 degrees two-theta, and 15.1 ± 0.2. In some embodiments, Compound 33 Form B is characterized by an X-ray powder diffractogram having (a) signais at 20.2 ± 0.2 degrees two-theta, 9.2 ± 0.2 degrees two-theta, 4.5 ± 0.2 degrees two-theta, and I5.l ± 0.2; and (b) at least one, at least two, at least three, at least four, at least five, at least six, at least eight, or at least ten signais selected from 9.9 ± 0.2 degrees two-theta, 11.0 ± 0.2 degrees two-theta, 12.7 ± 0.2 degrees two-theta, 14.3 ± 0.2 degrees two-theta, 16.2 ± 0.2 degrees two-theta, 16.8 ± 0.2 degrees two-theta, 17.1 ± 0.2 degrees two-theta, 18.1 ± 0.2 degrees two-theta, 18.4 ± 0.2 degrees two-theta, 19.8 ± 0.2 degrees two-theta, 20.6 ± 0.2 degrees two-theta, 21.4 ± 0.2 degrees two-theta, 22.3 ± 0.2 degrees two-theta, 23.6 ± 0.2 degrees twotheta, 24.7 ±0.2 degrees two-theta, 26.6 ±0.2 degrees two-theta, 27.4 ± 0.2 degrees two-theta, and 28.9 ± 0.2 degrees two-theta.

In some embodiments Compound 33 Form B is characterized by an X-ray powder diffractogram substantially similar to FIG. 2A.

In some embodiments, Compound 33 Form B is characterized as having a ^I3C ssNMR spectrum with 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. In some embodiments, Compound I sodium sait hydrate Form B is characterized as having a ¹³C ssNMR spectrum with 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. In some embodiments, Compound 33 Form B is characterized as having a ^!3C 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. In some embodiments, Compound 33 Form B is characterized as having a ¹³C 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. In some embodiments, Compound 33 Form B is characterized as having a ^l3C 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. In some embodiments, Compound 33 Form B is characterized as having a ¹³C ssNMR spectrum with at 114 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 i 0.2 ppm, 120.4 ± 0.2 ppm, 100.9 ± 0.2 ppm, 34.1 ± 0.2 ppm, and 31.9 ± 0.2 ppm. In some embodiments, Compound 33 Form B is characterized as having a ¹³C 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. In some embodiments, Compound 33 Form B is characterized by a ^l3C ssNMR spectrum substantially similar to FIG. 2B.

In some embodiments, Compound 33 Form B is characterized as having a ⁱ⁹F ssNMR spectrum with a peak at one or more of -110.2 ± 0.2 ppm, 111.6 ± 0.2 ppm, and -115.6 ± 0.2 ppm. In some embodiments, Compound 33 Form B is characterized as having a ^HF ssNMR spectrum with peaks at -110.2 ± 0.2 ppm, 111.6 ± 0.2 ppm, and -115.6 ± 0.2 ppm. In some embodiments, Compound 33 Form B is characterized by a ¹⁹F ssNMR spectrum substantially similar to FIG. 2C.

Another aspect of the invention provides a composition comprising Compound 33 Form B. In some embodiments, the composition of the invention comprises substantially pure crystalline Compound 33 Form B. In some embodiments, the composition consists essentially of Compound 33 Form B.

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

3. Compound 33 DCM Solvaté Form A

In some embodiments, Compound 33 îs a crystalline solid comprising of crystalline DCM Solvaté Form A. In some embodiments, the crystalline solid comprises of 30% to 99% crystalline Compound 33 DCM Solvaté Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 40% to 99% Compound 33 DCM Solvaté Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 50% to 99% Compound 33 DCM Solvaté Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 60% to 99% Compound 33 DCM Solvaté Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 70% to 99% Compound 33 DCM Solvaté Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 75% to 99% Compound 33 DCM Solvaté Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 80% to 99% Compound 33 DCM Solvaté Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 85% to 99% Compound 33 DCM Solvaté Form A relative to the total weight of solid Compound 33. In some embodiments, the 115 crystalline solid comprises of 90% to 99% Compound 33 DCM Solvaté Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 95% to 99% Compound 33 DCM Solvaté Form A relative to the total weight of solid Compound 33,

Thus, in some embodiments, Compound 33 DCM Solvaté Form A is substantially crystalline. In some embodiments, Compound 33 DCM Solvaté Form A is substantially pure crystalline. In some embodiments, Compound 33 Form A is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation. FIG. 3A provides an X-ray powder diffractogram of Compound 33 DCM Solvaté Form A at room température.

In some embodiments, Compound 33 DCM Solvaté Form A is characterized b y an X-ray powder diffractogram having signais at one or more of 20.9 ± 0.2 degrees two-theta, 18.3 ± 0.2 degrees two-theta, and 14.4 ± 0.2 degrees two-theta. In some embodiments, Compound 33 DCM Solvaté Form A is characterized by an X-ray powder diffractogram having signais at 20.9 ± 0.2 degrees two-theta, 18.3 ± 0.2 degrees two-theta, and 14.4 ± 0.2 degrees two-theta. In some embodiments, Compound 33 DCM Solvaté Form A is characterized by an X-ray powder diffractogram having (a) signais at 20.9 ± 0.2 degrees two-theta, 18.3 ± 0.2 degrees two-theta, and 14.4 ± 0.2 degrees two-theta; and (b) at least one, at least two, at least three, at least four, at least five, at least six, at least eight, or at least ten signais selected from 7.1 ± 0.2 degrees twotheta, 8.8 ± 0.2 degrees two-theta, 9.0 ± 0.2 degrees two-theta, 10.1 ± 0.2 degrees two-theta, 13.3 ± 0.2 degrees two-theta, 13.9 ± 0.2 degrees two-theta, 17.2 ± 0.2 degrees two-theta, 20.3 ± 0.2 degrees two-theta, 21.7 ± 0.2 degrees two-theta, 22.6 ± 0.2 degrees two-theta, 22.8 ± 0.2 degrees two-theta, 23.4 ± 0.2 degrees two-theta, 24.0 ± 0.2 degrees two-theta, 26.6 ± 0.2 degrees twotheta, 27.1 ± 0.2 degrees two-theta, 27.7 ± 0.2 degrees two-theta, 28.3 ± 0.2 degrees two-theta.

In some embodiments Compound 33 DCM Solvaté Form A is characterized by an X-ray powder diffractogram substantially similar to FIG. 3A.

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

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

4. Compound 33 Hydrate Form A

116 ln some embodiments, Compound 33 is a crystalline solid comprising of crystalline Hydrate Form A. In some embodiments, the crystalline solid comprises of 30% to 99% crystalline Compound 33 Hydrate Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 40% to 99% Compound 33 Hydrate Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 50% to 99% Compound 33 Hydrate Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 60% to 99% Compound 33 Hydrate Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 70% to 99% Compound 33 Hydrate Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 75% to 99% Compound 33 Hydrate Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 80% to 99% Compound 33 Hydrate Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 85% to 99% Compound 33 Hydrate Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 90% to 99% Compound 33 Hydrate Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 95% to 99% Compound 33 Hydrate Form A relative to the total weight of solid Compound 33.

Thus, în some embodiments, Compound 33 Hydrate Form A is substantially crystalline. In some embodiments, Compound 33 Hydrate Form A is substantially pure crystalline. In some embodiments, Compound 33 Hydrate Form A îs characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu K a radiation. FIG. 4A provides an X-ray powder diffractogram of Compound 33 Hydrate Form A at room température.

In some embodiments, Compound 33 Hydrate Form A is characterized by an X-ray powder diffractogram having signais at one or more of 19.5 ± 0.2 degrees two-theta, 10.4 ± 0.2 degrees two-theta, and 16.6 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Hydrate Form A is characterized by an X-ray powder diffractogram having signais at 19.5 ± 0.2 degrees two-theta, 10.4 ± 0.2 degrees two-theta, and 16.6 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Hydrate Form A is characterized b y an X-ray powder diffractogram having (a) signais at 19.5 ± 0.2 degrees two-theta, 10.4 ± 0.2 degrees two-theta, and 16.6 ± 0.2 degrees two-theta; and (b) at at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or ten signais selected from 13.6 ± 0.2 degrees two-theta, 18.4 ± 0.2 degrees two-theta, 17.5 ± 0.2 degrees two-theta, 18.9 ± 0.2 degrees two-theta, 20.8 ± 0.2 degrees two-theta, 21.1 ± 0.2 degrees two-theta, 21.4 ± 0.2 degrees two-theta, 21.6 ± 0.2 degrees two117 thêta, 21.8 ± 0.2 degrees two-theta, and 24.8 ± 0.2 degrees two-theta, In some embodiments Compound 33 Hydrate Form A is characterized by an X-ray powder diffractogram substantially similar to FIG. 4A.

In some embodiments, Compound 33 Hydrate Form A is characterized by a triclinic crystal system, a P-1 space group, and the foilowing unit cell dimensions measured at 100 K on a Bruker diffractiometer equipped with Cu K_w radiation (λ=1.54178 Â) and a CMOS detector:

a(Â)	9.98 ±.01
b (Â)	10.42 ± .01
c(Â)	11.30 ± .01
«o	74.06 ± .02
β(°)	78.91 ± .02
γ(°)	84.14 ± .02
V (Â3)	1107.3 ± 1.8
Z/Z'	2/1

In some embodiments, Compound 33 Hydrate Form A is characterized as having a ^lîC ssNMR spectrum with 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. In some embodiments, Compound 33 Hydrate Form A is characterized as having a ^l3C ssNMR spectrum with 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. In some embodiments, Compound 33 Hydrate Form A is characterized as having a ^l3C ssNMR spectrum with 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. In some embodiments, Compound 33 Hydrate Form A is characterized as having a ¹³C ssNMR spectrum with 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. In some embodiments, Compound 33 Hydrate Form A is characterized as having a ^l3C ssNMR spectrum with 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. In some embodiments, Compound 33 Hydrate Form A is characterized as having a ¹³C 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. In some embodiments, Compound 33 Hydrate Form A is characterized as having a ¹³C ssNMR spectrum with 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. In some embodiments, Compound 33 Hydrate Form A characterized as having a ¹³C 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. In some embodiments, Compound 33 Hydrate Form A is characterized by a ^l3C NMR spectrum

118 having a signal at at least at least four, at least six, at least eight, at least ten, at least twelve, or at least fifteen ppm values chosen from 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 ± 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. In some embodiments, Compound 33 Hydrate Form A îs characterized by a ¹³C ssNMR spectrum substantially similar to FIG. 4B.

In some embodiments, Compound 33 Hydrate Form A is characterized by a ^l9F NMR spectrum having a signal at -103.1 ± 0.2 ppm. In some embodiments, Compound 33 Hydrate Form A is characterized by a ^l9F ssNMR spectrum substantially similar to FIG. 4C.

Another aspect of the invention provides a composition comprising Compound 33 Hydrate Form A. In some embodiments, the composition of the invention comprises substantially pure crystalline Compound 33 Hydrate Form A. In some embodiments, the composition consists essentially of Compound 33 Hydrate Form A.

Another aspect of the invention provides a method of making Compund 33 Hydrate Form A. En some embodiments, Compound 33 Hydrate A is prepared by adding water to Compound 33 Form A, stirring for about two weeks and isolating the solid form.

5. Compound MeOH/HzO Solvate/Hydrate Form A

In some embodiments, Compound 33 is a crystalline solid comprising of crystalline MeOH/HjO Solvate/Hydrate Form A. In some embodiments, the crystalline solid comprises of 30% to 99% crystalline Compound 33 Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 40% to 99% Compound 33 MeOH/H₂O Solvate/Hydrate Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 50% to 99% Compound 33 MeOH/H₂O Solvate/Hydrate Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 60% to 99% Compound 33 MeOH/H₂O Solvate/Hydrate Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 70% to 99% Compound 33 MeOH/H₂O Solvate/Hydrate Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 75% to 99% Compound 33 MeOH/H₂O Solvate/Hydrate Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 80% to 99% Compound 33 MeOH/H₂O Solvate/Hydrate Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 85% to 99% Compound 33 MeOH/H₂O Solvate/Hydrate Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 90% to 99% Compound 33 MeOH/H₂O 119

Solvate/Hydrate Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 95% to 99% Compound 33 MeOH/H₂O Solvate/Hydrate Form A relative to the total weight of solid Compound 33.

Thus, în some embodiments, Compound 33 MeOH/H₂O Solvate/Hydrate Form A is substantially crystalline. In some embodiments, Compound 33 MeOH/H₂O Solvate/Hydrate Form A is substantially pure crystalline. In some embodiments, Compound 33 MeOH/H₂O Solvate/Hydrate Form A is characterized by an X-ray powder diffractogram generated by an Xray powder diffraction analysis with an incident beam of Cu Ka radiation. FIG. 5A provides an X-ray powder diffractogram of Compound 33 MeOH/H₂O Solvate/Hydrate Form A at room température.

In some embodiments, Compound 33 MeOH/H₂O Solvate/Hydrate Form A is characterized by an X-ray powder diffractogram having signais at 16.6 ± 0.2 degrees two-theta and 17.4 ± 0.2 degrees two-theta. In some embodiments, Compound 33 MeOH/H₂O Solvate/Hydrate Form A is characterized by an X-ray powder diffractogram having signais at (a) 16.6 ± 0.2 degrees two-theta and 17.4 ± 0.2 degrees two-theta and (b) one or more of 10.4 ± 0.2 degrees two-theta, 18.2 ± 0.2 degrees two-theta, and 19.4 ± 0.2 degrees two-theta. In some embodiments, Compound 33 MeOH/H₂O Solvate/Hydrate Form A is characterized by an X-ray powder diffractogram having signais at 10.4 ± 0.2 degrees two-theta, 16.6 ± 0.2 degrees twotheta, 17.4 ± 0.2 degrees two-theta, 18.2 ± 0.2 degrees two-theta, and 19.4 ± 0.2 degrees twotheta.

In some embodiments, Compound 33 MeOH/H₂O Solvate/Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least four, at least six, at least eight, or at least ten two-theta values chosen 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, Compound 33 MeOH/H₂O Solvate/Hydrate Form A is characterized by an X-ray powder diffractogram substantially similar to FIG. 5A.

In some embodiments, Compound 33 MeOH/H₂O Solvate/Hydrate Form A is characterized by a triclinic crystal system, a P-l space group, and the following unit cell dimensions measured at 100 K on a Bruker diffractiometer equipped with Cu K_a radiation (λ=1 .54178 Â) and a CMOS detector:

120

a(Â)	10.02 ± .01
b (À)	10.43 ± .01
c(Â)	11.25 ±.01
a(°)	74.50 ± .01
P(°)	79.62 ± .01
ï(°)	84.98 ± .01
V(Â3)	1113.5 ± 1.8
Z/Z'	2/1

Another aspect of the invention provides a composition comprising Compound 33 MeOH/HjO Solvate/Hydrate Form A. In some embodiments, the composition of the invention comprises substantially pure crystalline Compound 33 MeOH/H₂O Solvate/Hydrate Form A. In some embodiments, the composition consists essentially of Compound 33 MeOH/H₂O Solvate/Hydrate Form A,

Another aspect of the invention provides a method of making Compund 33 MeOH/H₂O Solvate/Hydrate Form A. In some embodiments, Compound 33 MeOH/H₂O Solvate/Hydrate A is prepared b y adding MeOH to Compound 33 Form A, stirring for about two weeks at ambient temperature, and isolating the solid fonn.

6. Compound 33 Form C

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

I2l

Thus, in some embodiments, Compound 33 Form C is substantially crystalline. In some embodiments, Compound 33 Form C is substantially pure crystalline. Tn some embodiments, Compound 33 Form C is characterized by an X-ray powder diffractogram generated b y an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation. FIG. 6A provides an Xray powder diffractogram of Compound Form C at room température.

In some embodiments, Compound 33 Form C is characterized by an X-ray powder diffractogram having signais at 9.4 ± 0.2 degrees two-theta and 15.4 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Form C is characterized by an X-ray powder diffractogram having signais at (a) 9.4 ± 0.2 degrees two-theta and 15.4 ± 0.2 degrees two-theta and (b) 19.0 ± 0.2 degrees two-theta and/or 21.0 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Fonn C is characterized by an X-ray powder diffractogram having signais at 9.4 ± 0.2 degrees two-theta, 15.4 ± 0.2 degrees two-theta, 19.0 ± 0.2 degrees two-theta, and 21.0 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Form C is characterized by an X-ray powder diffractogram having a signal at at least four, at least six, or eight two-theta values chosen from 9.4 ± 0.2 degrees two-theta, 15.4 ± 0.2 degrees two-theta, 18.2 ± 0.2 degrees two-theta, 19.0 ± 0.2 degrees two-theta, 19.6 ± 0.2 degrees two-theta, 20.2 ± 0.2 degrees two-theta, 21.0 ± 0.2 degrees two-theta, and 21.5 ± 0.2 degrees two-theta. in some embodiments, Compound 33 Form C is characterized by an X-ray powder diffractogram substantially similar to FIG. 6A.

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

Another aspect of the invention provides a method of making Compund 33 Form C. In some embodiments, Compound 33 Form C is prepared b y mixing a sample of stock sol ution (prepared by dissolving Compound 33 Form A in MeOH, warming to about 45°C and then about 50°C) în MeOH/H2O (2:1 by volume) and stirring at about 45°C for about 3 days and isolating the solid fonn.

7. Compound 33 Form D

In some embodiments, Compound 33 is a crystalline solid comprising of crystalline Form D. In some embodiments, the crystalline solid comprises of 30% to 99% crystalline Compound 33 Form D relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 40% to 99% Compound 33 Form D relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 50% to 99% Compound 33 Fonn D relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 60% to 99% Compound 33 Form D relative to the total weight 122 of solid Compound 33. In some embodiments, the crystalline solid comprises of 70% to 99% Compound 33 Form D relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 75% to 99% Compound 33 Fonn D relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 80% to 99% Compound 33 Fonn D relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 85% to 99% Compound 33 Fonn D relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 90% to 99% Compound 33 Fonn D relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 95% to 99% Compound 33 Form D relative to the total weight of solid Compound 33.

Thus, in some embodiments, Compound 33 Form D îs substantially crystalline. In some embodiments, Compound 33 Fonn D is substantially pure crystalline. In some embodiments, Compound 33 Fonn D is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation. FIG. 7A provides an Xray powder diffractogram of Compound Fonn D at room temperature.

In some embodiments, Compound 33 Fonn D is characterized by an X-ray powder diffractogram having signais at 14.4 ± 0.2 degrees two-theta and 24.0 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Fonn D is characterized b y an X-ray powder diffractogram having signais at (a) 14.4 ± 0.2 degrees two-theta and 24.0 ± 0.2 degrees two-theta and (b) 10.4 ± 0.2 degrees two-theta and/or 20.5 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Form D îs characterized by an X-ray powder diffractogram having signais at 10.4 ± 0.2 degrees two-theta, 14.4 ± 0.2 degrees two-theta, 20.5 ± 0.2 degrees two-theta, and 24.0 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Form D is characterized by an X-ray powder diffractogram having a signal at at least four, at least six, at least eight, or at least ten two-theta values chosen from 7.8 ± 0.2 degrees two-theta, 8.2 ± 0.2 degrees two-theta, 8.6 ± 0.2 degrees two-theta, 10.4 ± 0.2 degrees two-theta, 13.7 ± 0.2 degrees two-theta, 14.4 ± 0.2 degrees twotheta, 15.3 ± 0.2 degrees two-theta, 18.6 ± 0.2 degrees two-theta, 18.9 ± 0.2 degrees two-theta, 20.1 ± 0.2 degrees two-theta, 20.5 ± 0.2 degrees two-theta, 21.9 ± 0.2 degrees two-theta, 24.0 4 0.2 degrees two-theta, and 24.3 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Form D is characterized by an X-ray powder diffractogram substantially similar to FIG. 7A.

Another aspect of the invention provides a composition comprising Compound 33 Form D. In some embodiments, the composition of the invention comprises substantially pure crystalline Compound 33 Form D. In some embodiments, the composition consists essentially of Compound 33 Form D.

123

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

8. Compound 33 Form E

In some embodiments, Compound 33 is a crystalline solid comprising of crystalline Form E. In some embodiments, the crystalline solid comprises of 30% to 99% crystalline Compound 33 Fonn E relative to the total weight of solid Compound 33. in some embodiments, the crystalline solid comprises of 40% to 99% Compound 33 Fonn E relative to the total weight of solid Compound 33. in some embodiments, the crystalline solid comprises of 50% to 99% Compound 33 Form E relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 60% to 99% Compound 33 Fonn E relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 70% to 99% Compound 33 Form E relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 75% to 99% Compound 33 Fonn E relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 80% to 99% Compound 33 Fonn E relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 85% to 99% Compound 33 Form E relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 90% to 99% Compound 33 Form E relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 95% to 99% Compound 33 Form E relative to the total weight of solid Compound 33.

Thus, in some embodiments, Compound 33 Fonn E is substantially crystalline. In some embodiments, Compound 33 Fonn E is substantially pure crystalline. In some embodiments, Compound 33 Fonn E is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ko radiation. FIG. 8A provides an Xray powder diffractogram of Compound Form E at room température.

In some embodiments, Compound 33 Form E is characterized by an X-ray powder diffractogram having signais at 16.2 ± 0.2 degrees two-theta and I7.9 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Form E is characterized by an X-ray powder diffractogram having signais at (a) 16.2 ± 0.2 degrees two-theta and 17.9 ± 0.2 degrees two-theta and (b) 12.6 ± 0.2 degrees two-theta and/or 20.7 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Fonn E is characterized b y an X-ray powder diffractogram having signais at 12.6 ± 0.2 degrees two-theta, 16.2 ± 0.2 degrees two-theta, 17.9 ± 0.2 degrees two-theta, and 20.7 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Fonn E is characterized by an X-ray powder 124 diffractogram having a signal at at least four, at least six, at least eight, at least ten, or at least twelve two-theta values chosen from 7.9 ± 0.2 degrees two-theta, 11.2 ± 0.2 degrees two-theta, 12.6 ± 0.2 degrees two-theta, 12.8 ± 0.2 degrees two-theta, 13.7 ± 0.2 degrees two-theta, 15.3 ± 0.2 degrees two-theta, 16.2 ± 0.2 degrees two-theta, 17.9 ± 0.2 degrees two-theta, 19.9 ± 0.2 degrees two-theta, 20.7 ± 0.2 degrees two-theta, 21.1 ±0.2 degrees two-theta, 22.5 ± 0.2 degrees two-theta, 22.8 ± 0.2 degrees two-theta, 24.1 ± 0.2 degrees two-theta, 25.0 ± 0.2 degrees twotheta, 27.0 ± 0.2 degrees two-theta, and 2S.9 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Form E is characterized by an X-ray powder diffractogram substantially similar to FIG. 8A

Another aspect of the invention provides a composition comprising Compound 33 Form E. In some embodiments, the composition of the invention comprises substantially pure crystalline Compound 33 Form E. In some embodiments, the composition consists essentially of Compound 33 Form E.

Another aspect of the invention provides a method of making Compund 33 Form E. In some embodiments, Compound 33 Form E is prepared by dissolving Compound 33 Form A in MeOH after warming to 45°C and then 5Ü°C, cooling solution and stirring in cold room for about 3 days, and îsolating the solid form.

9. Compound 33 Form F

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

125

Thus, in some embodiments, Compound 33 Form F is substantially crystalline. In some embodiments, Compound 33 Form F is substantially pure crystalline. In some embodiments, Compound 33 Form F is characterized by an X-ray powder diffractogram générâted by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation. FIG. 9A provides an Xray powder diffractogram of Compound Form F at room température.

In some embodiments, Compound 33 Form F is characterized by an X-ray powder diffractogram having a signal at one or more two-theta values selected from 8.6 ± 0.2 degrees two-tbeta, Î3.0 ± 0.2 degrees two-theta, and 23.0 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Form F is characterized by an X-ray powder diffractogram having signais at 8.6 ± 0.2 degrees two-theta, 13.0 ± 0.2 degrees two-theta, and 23.0 ± 0.2 degrees twotheta. In some embodiments, Compound 33 Form F is characterized by an X-ray powder diffractogram having a signal at ai least four, at least six, at least eight, at least ten, or at least twelve two-theta values chosen from 7.7 ± 0.2 degrees two-theta, 8.6 ± 0.2 degrees two-theta, 11.4 ± 0.2 degrees two-theta, 11.6 ± 0.2 degrees two-theta, 12.2 ± 0.2 degrees two-theta, 13.0 ± 0.2 degrees two-theta, 14.2 ± 0.2 degrees two-theta, 14.9 ± 0.2 degrees two-theta, 17.3 ± 0.2 degrees two-theta, 17.4 ± 0.2 degrees two-theta, 17.8 ± 0.2 degrees two-theta, 18.3 ± Ü.2 degrees two-theta, 19.0 ± 0.2 degrees two-theta, 20.4 ± 0.2 degrees two-theta, 21.4 ± 0.2 degrees twotheta, 21.6 ± 0.2 degrees two-theta, 22.6 ± 0.2 degrees two-theta, 22.8 ± 0.2 degrees two-theta, 23.0 ± 0.2 degrees two-theta, 23.3 ± 0.2 degrees two-theta, 24.0 ± 0.2 degrees two-theta, 24.2 ± 0.2 degrees two-theta, 24.9 ± 0.2 degrees two-theta, 25.8 ± 0.2 degrees two-theta, and 26.4 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Form F is characterized by an X-ray powder diffractogram substantially similar to FIG. 9A.

Another aspect of the invention provides a composition comprising Compound 33 Form F. In some embodiments, the composition of the invention comprises substantially pure crystalline Compound 33 Form F. In some embodiments, the composition consists essentîally of Compound 33 Form F.

Another aspect of the invention provides a method of making Conipund 33 Fonn F. In some embodiments, Compound 33 Fonn F is prepared by adding Compound 33 THF Solvaté Form A to EtOH, stirring and slurrifying at about 20 °C ovemight, and isolating the solid fonn.

10. Compound 33 Form G

In some embodiments, Compound 33 is a crystalline solid comprising of crystalline Fonn G. In some embodiments, the crystalline solid comprises of 30% to 99% crystalline Compound 33 Form G relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 40% to 99% Compound 33 Fonn G relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 50% to 99% 126

Compound 33 Form G relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 60% to 99% Compound 33 Form G relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 70% to 99% Compound 33 Form G relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 75% to 99% Compound 33 Form G relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 80% to 99% Compound 33 Form G relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 85% to 99% Compound 33 Form G relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 90% to 99% Compound 33 Form G relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 95% to 99% Compound 33 Form G relative to the total weight of solid Compound 33.

Thus, in some embodiments, Compound 33 Form G is substantially crystalline. In some embodiments, Compound 33 Form G is substantially pure crystalline. In some embodiments, Compound 33 Form G is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Kct radiation. FIG. 10A provides an Xray powder diffractogram of Compound Form G at room température.

In some embodiments, Compound 33 Form G is characterized by an X-ray powder diffractogram having a signal at one or more two-theta values selected from 19.8 ± 0.2 degrees two-theta, 20.2 ± 0.2 degrees two-theta, and 20.8 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Form G is characterized by an X-ray powder diffractogram having signais at 19.8 ± 0.2 degrees two-theta, 20.2 ± 0.2 degrees two-theta, and 20.8 ± 0.2 degrees twotheta. In some embodiments, Compound 33 Form G is characterized by an X-ray powder diffractogram having a signal at at least four, at least six, at least eight, at least ten, or at least twelve two-theta values chosen from 9.3 ± 0.2 degrees two-theta, 10.8 ± 0.2 degrees two-theta, 11.5±0.2 degrees two-theta, 12.6±0.2 degrees two-theta, 17.5±0.2 degrees two-theta, 18.4± 0.2 degrees two-theta, 19.1 ± 0.2 degrees two-theta, 19.8 ± 0.2 degrees two-theta, 20.2 ± 0.2 degrees two-theta, 20.8 ± 0.2 degrees two-theta, 21.6 ± 0.2 degrees two-theta, 22.6 ± 0.2 degrees two-theta, 23.4 ± 0.2 degrees two-theta, 24.2 ± 0.2 degrees two-theta and 25.5 ± 0.2 degrees twotheta. In some embodiments, Compound 33 Form G is characterized by an X-ray powder diffractogram substantially similar to FIG, 10A.

Another aspect of the invention provides a composition comprising Compound 33 Fonn G. In some embodiments, the composition of the invention comprises substantially pure crystalline Compound 33 Form G. In some embodiments, the composition consists essentially of Compound 33 Form G.

127

Another aspect of the invention provides a method of making Compund 33 Form G. In some embodiments, Compound 33 Form G is prepared b y adding Compound 33 Form A to EtOH, stirring for about one day at about 5°C, and isolating the solid form.

IL Compound 33 Form H

In some embodiments, Compound 33 is a crystalline solid comprising of crystalline Form H. In some embodiments, the crystalline solid comprises of 30% to 99% crystalline Compound 33 Form H relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 40% to 99% Compound 33 Form H relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 50% to 99% Compound 33 Form H relative to the total weight of solid Compound 33. Tn some embodiments, the crystalline solid comprises of 60% to 99% Compound 33 Form H relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 70% to 99% Compound 33 Form H relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 75% to 99% Compound 33 Form FI relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 80% to 99% Compound 33 Fonn H relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 85% to 99% Compound 33 Fonn H relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 90% to 99% Compound 33 Form H relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 95% to 99% Compound 33 Form H relative to the total weight of solid Compound 33.

Thus, in some embodiments, Compound 33 Form II is substantially crystalline. In some embodiments, Compound 33 Form H is substantially pure crystalline. In some embodiments, Compound 33 Form H is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation. FIG. 11A provides an Xray powder diffractogram of Compound Form H at room température.

In some embodiments, Compound 33 Form H is characterized by an X-ray powder diffractogram having a signal at one or more two-theta values selected from 5.0 ± 0.2 degrees two-theta, 18.3 ± 0.2 degrees two-theta, and 19.5 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Form H is characterized by an X-ray powder diffractogram having signais at 5.0 ± 0.2 degrees two-theta, 18.3 ± 0.2 degrees two-theta, and 19.5 ± 0.2 degrees twotheta. In some embodiments, Compound 33 Form H is characterized by an X-ray powder diffractogram having a signal at at least four, at least five, at least six, or at least seven two-theta values chosen 5.0 ± 0.2 degrees two-theta, 8.8 degrees two-theta, 15.0 degrees two-theta, 17.6 degrees two-theta, 18.3 ± 0.2 degrees two-theta, 18.9 degrees two-theta, 19.5 ± 0.2 degrees two128 thêta, and 20.7 degrees two-theta. In some embodiments, Compound 33 Form H is characterized by an X-ray powder diffractogram having signais at 5.0 ± 0.2 degrees two-theta, 8.8 degrees two-theta, 15.0 degrees two-theta, 17.6 degrees two-theta, 18.3 ± 0.2 degrees two-theta, 18.9 degrees two-theta, 19.5 ± 0.2 degrees two-theta, and 20.7 degrees two-theta. In some embodiments, Compound 33 Form H is characterized by an X-ray powder diffractogram substantially similar to FIG. 11 A,

Another aspect of the invention provides a composition comprising Compound 33 Form H. In some embodiments, the composition of the invention comprises substantially pure crystalline Compound 33 Form H. In some embodiments, the composition consists essentially of Compound 33 Form H.

Another aspect of the invention provides a method of making Compund 33 Form H. In some embodiments, Compound 33 Fonn H is prepared by dissoiving Compound 33 Form A in EtOH, placing the solution in a water bath at room tempreature for enough time to ailow water vapor to interact with solution, and isolating the solid fonn.

12. Compound 33 Form I

In some embodiments, Compound 33 is a crystalline solid comprising of crystalline Fonn I. In some embodiments, the crystalline solid comprises of 30% to 99% crystalline Compound 33 Fonn I relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 40% to 99% Compound 33 Fonn 1 relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 50% to 99% Compound 33 Fonn I relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 60% to 99% Compound 33 Fonn I relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 70% to 99% Compound 33 Fonn I relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 75% to 99% Compound 33 Form I relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 80% to 99% Compound 33 Fonn I relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 85% to 99% Compound 33 Fonn I relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 90% to 99% Compound 33 Fonn I relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 95% to 99% Compound 33 Form I relative to the total weight of solid Compound 33,

Thus, in some embodiments, Compound 33 Form I is substantially crystalline. In some embodiments, Compound 33 Fonn I is substantially pure crystalline. In some embodiments, Compound 33 Fonn I is characterized by an X-ray powder diffractogram generated by an X-ray 129 powder diffraction analysis with an incident beam of Cu Ka radiation. FIG. 12C provides an Xray powder diffractogram of Compound Form 1 at room température.

In some embodiments, Compound 33 Form I is characterized by an X-ray powder diffractogram having a signal at one or more two-theta values selected from 9.3 ± 0.2 degrees two-theta, 19.0 ± 0.2 degrees two-theta, and 21.0 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Form 1 is characterized by an X-ray powder diffractogram having signais at 9.3 ± 0.2 degrees two-theta, 19.0 ± 0.2 degrees two-theta, and 21.0 ± 0.2 degrees twotheta. In some embodiments, Compound 33 Form I is characterized by an X-ray powder diffractogram having a signal at at least four, at least five, or at least six two-theta values chosen from 9.3 ± 0.2 degrees two-theta, 15.4 ± 0.2 degrees two-theta, 18.3 ± 0.2 degrees two-theta, 18.6 ± 0.2 degrees two-theta, 19.0 ± 0.2 degrees two-theta, 20.2 ± 0.2 degrees two-theta, and 21.0 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Form I is characterized by an X-ray powder diffractogram having signais at 9.3 ± 0.2 degrees two-theta, 15.4 ± 0.2 degrees two-theta, 18.3 ± 0.2 degrees two-theta, 18.6 ± 0.2 degrees two-theta, 19.0 ± 0.2 degrees twotheta, 20.2 ± 0.2 degrees two-theta, and 21.0 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Fonn I is characterized by an X-ray powder diffractogram substantially similar to FIG. 12C

Another aspect of the invention provides a composition comprising Compound 33 Form I. In some embodiments, the composition of the invention comprises substantially pure crystalline Compound 33 Fonn 1. In some embodiments, the composition consists essentially of Compound 33 Form I.

Another aspect of the invention provides a method of making Compund 33 Form I. In some embodiments, Compound 33 Fonn I is prepared by distillative crystallization of Compound 33 from 2 Me-THF/THF to EtOH/H2O, stîrring overnight, drying in a vacuum oven with nigrogen at about 66 °C overnight, and isolating the solid form.

13. Compound 33 THF Solvaté Form A

In some embodiments, Compound 33 is a crystalline solid comprising of crystalline THF Solvaté Form A. In some embodiments, the crystalline solid comprises of 30% to 99% crystalline Compound 33 THF Solvaté Fonn A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 40% to 99% Compound 33 THF Solvaté Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 50% to 99% Compound 33 THF Solvaté Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 60% to 99% Compound 33 THF Solvaté Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 70% to 99% Compound 33 THF 130

Solvaté Fonn A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 75% to 99% Compound 33 THF Solvaté Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 80% to 99% Compound 33 THF Solvaté Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 85% to 99% Compound 33 THF Solvaté Fonn A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 90% to 99% Compound 33 THF Solvaté Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 95% to 99% Compound 33 THF Solvaté Form A relative to the total weight of solid Compound 33.

Thus, in some embodiments, Compound 33 THF Solvaté Form A îs substantially crystalline. In some embodiments, Compound 33 THF Solvaté Fonn A is substantially pure crystalline. In some embodiments, Compound 33 THF Solvaté Fonn A is characterized by an Xray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation. FIG. 13A provides an X-ray powder diffractogram of Compound THF Solvaté Fonn A at room température.

In some embodiments, Compound 33 TFIF Solvaté Form A is characterized by an X-ray powder diffractogram having a signal at 8.2 ± 0.2 degrees two-theta and/or 8.5 ± 0.2 degrees two-theta. In some embodiments, Compound 33 THF Solvaté Fonn A is characterized by an Xray powder diffractogram having a signal at 19.1 ± 0.2 degrees two-theta and/or 19.4 ± 0.2 degrees two-theta. In some embodiments, Compound 33 THF Solvaté Fonn A is characterized by an X-ray powder diffractogram having signais at 8.2 ± 0.2 degrees two-theta, 8.5 ± 0.2 degrees two-theta, 19.1 ± 0.2 degrees two-theta, and 19.4 ± 0.2 degrees two-theta. In some embodiments, Compound 33 THF Solvaté Form A is characterized by an X-ray powder diffractogram having a signal at at least four, at least six, at least eight, or at least ten two-theta values chosen from 8.2 ± 0.2 degrees two-theta, 8.5 ± 0.2 degrees two-theta, 9.5 ± 0.2 degrees two-theta, 11.3 ± 0.2 degrees two-theta, 17.1 ± 0.2 degrees two-theta, 17.8 ± 0.2 degrees twotheta, 19.1 ± 0.2 degrees two-theta, 19.4 ± 0.2 degrees two-theta, 20.5 ± 0.2 degrees two-theta, 21.1 ± 0.2 degrees two-theta, 21.2 ± 0.2 degrees two-theta, 21.5 ± 0.2 degrees two-theta, 22.9 ± 0.2 degrees two-theta, and 23.1 ± 0.2 degrees two-theta. In some embodiments, Compound 33 THF Solvaté Form A is characterized by an X-ray powder diffractogram substantially similar to FIG. 13A.

In some embodiments, Compound 33 THF Solvaté Fonn A is characterized by a orthorhombic crystal system, a Pca2i space group, and the following unit cell dimensions

131 measured at 100 K on a Bruker diffractiometer equipped with Cu K_a radiation (λ=1.54178 Â) and a CMOS detector:

a(Â)	25.12 ± .01
b (Â)	11.98 ± .01
c(A)	17.7 ±0.1
a(°)	90
β(°)	90
γ(°)	90
V (Â3)	5327 ± 30
Z/Z'	4/2

In some embodiments, Compound 33 THF Solvaté Fonn A is characterized as having a ⁱ³C ssNMR spectrum with 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. In some embodiments, Compound 33 THF Solvaté Fonn A is characterized as having a ^,3C ssNMR spectrum with 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. In some embodiments, Compound 33 THF Solvaté Form A is characterized as having a ¹³C ssNMR spectrum with 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. In some embodiments, Compound 33 THF Solvaté Fonn A is characterized as having a ^l3C ssNMR spectrum with at least four peaks selected from: 165.8 ± Ü.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. In some embodiments, Compound 33 THF Solvaté Form A is characterized as having a ^l3C ssNMR spectrum with at least five peaks selected from: 165.8 ± 0.2, 140.0 ± 0.2, 133.9 ± 0.2, 121.2 ± Û.2, 114.3 ± 0.2, 96.1 ± 0.2, 69.0 ± 0.2, 25.7 ± 0.2 ppm and 25.3 ± 0.2 ppm. In some embodiments, Compound 33 THF Solvaté Form A is characterized as having a ^l3C 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. In some embodiments, Compound 33 THF Solvaté Form A is characterized as having a ^l3C 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. In some embodiments, Compound 33 THF Solvaté Form A characterized as having a ^l3C 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

132

25.3 ± 0.2 ppm. In some embodiments, Compound 33 THF Solvaté Form A is characterized by a ^l3C ssNMR spectrum substantially similar to FIG. 13B.

In some embodiments, Compound 33 THF Solvaté Fonn A is characterized by a ^l9F NMR spectrum having a peak at -HO.5 ± 0.2 ppm and/or -H3.0 ± 0.2 ppm. In some 5 embodiments, Compound 33 THF Solvaté Form A is characterized by a ^!9F ssNMR spectrum substantially similar to FIG. 13C.

Another aspect of the invention provides a composition comprising Compound 33 THF Solvaté Form A. In some embodiments, the composition of the invention comprises substantially pure crystalline Compound 33 THF Solvaté Fonn A. In some embodiments, the 10 composition consists essentially of Compound 33 THF Solvaté Form A.

Another aspect ofthe invention provides methods of making Compound 33 THF Solvaté Form A. In some embodiments, Compound 33 THF Solvaté Form A is prepared b y adding Compound 33 Form A to THF în a container, sealing the container and storing at room température for about 2 weeks, and isolating the solid form.

14. Compound 33 Form J

In some embodiments, Compound 33 is a crystalline solid comprising of crystalline Fonn J. In some embodiments, the crystalline solid comprises of 30% to 99% crystalline Compound 33 Fonn J relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 40% to 99% Compound 33 Fonn J relative to the total weight of 20 solid Compound 33. In some embodiments, the crystalline solid comprises of 50% to 99% Compound 33 Form J relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 60% to 99% Compound 33 Fonn J relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 70% to 99% Compound 33 Fonn J relative to the total weight of solid Compound 33. In some embodiments, 25 the crystalline solid comprises of 75% to 99% Compound 33 Fonn J relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 80% to 99% Compound 33 Fonn J relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 85% to 99% Compound 33 Fonn J relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 90% to 99% 30 Compound 33 Fonn J relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 95% to 99% Compound 33 Form J relative to the total weight of solid Compound 33.

Thus, in some embodiments, Compound 33 Fonn J is substantially crystalline. In some embodiments, Compound 33 Form J is substantially pure crystalline. In some embodiments, 35 Compound 33 Fonn J is characterized by an X-ray powder diffractogram generated b y an X-ray 133 powder diffraction analysis with an incident beam of Cu Ko radiation. FIG. 14A provides an Xray powder diffractogram of Compound Form .I at room température.

In some embodiments, Compound 33 Form J is characterized by an X-ray powder diffractogram having signais at one or more of 6.6 ± 0.2 degrees two-theta, 7.5 ± 0.2 degrees two-theta, and 15.0 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Form J is characterized by an X-ray powder diffractogram having signais at 6.6 ± 0.2 degrees two-theta, 7.5 ± 0.2 degrees two-theta, and 15.0 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Form J îs characterized by an X-ray powder diffractogram having (a) signais at 6.6 ± 0.2 degrees two-theta, 7.5 ± 0.2 degrees two-theta, and 15.0 ± 0.2 degrees two-theta; and (b) a signal at at least one, at least two, at least three, at least four, at least six, at least eight, or at least ten two-theta values chosen from 10.3 ± 0.2 degrees two-theta, 15.6 ± 0.2 degrees twotheta, 16.0 ± 0.2 degrees two-theta, 16.8 ± 0.2 degrees two-theta, 17.9 ± 0.2 degrees two-theta, 19.4 ± 0.2 degrees two-theta, 19.9 ± 0.2 degrees two-theta, 20.1 ± 0.2 degrees two-theta, 20.6 ± 0.2 degrees two-theta, 20.8 ± 0.2 degrees two-theta, 21.4 ± 0.2 degrees two-theta, 21.7 ± 0.2 degrees two-theta, and 22.5 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Form J îs characterized by an X-ray powder diffractogram substantially similar to FIG. 14A.

Another aspect of the invention provides a composition comprising Compound 33 Form J. In some embodiments, the composition of the invention comprises substantially pure crystalline Compound 33 Form J. In some embodiments, the composition consists essentially of Compound 33 Form J.

Another aspect of the invention provides methods of making Compound 33 Form J. In some embodiments, Compound 33 Form J îs prepared by adding Compound 33 Form A to THF:EtOH: Water (6:1:1 by volume) in a container, slurrying for about 1 hour, filtering, and then addding a polymer mixture comprising one or more polymers selected from polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinylchloride (PVC), hypromellose (HPMC), methyl cellulose (MC), stirring at room température for about a day, and isolating the solid form.

15. Compound 33 Form K

In some embodiments, Compound 33 is a crystalline solid comprising of crystalline Form K. In some embodiments, the crystalline solid comprises of 30% to 99% crystalline Compound 33 Form K relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 40% to 99% Compound 33 Form K relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 50% to 99% Compound 33 Form K relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 60% to 99% Compound 33 Form K relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 70% to 99% 134

Compound 33 Form K relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 75% to 99% Compound 33 Form K relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 80% to 99% Compound 33 Form K relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 85% to 99% Compound 33 Form K relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 90% to 99% Compound 33 Form K relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 95% to 99% Compound 33 Form K relative to the total weight of solid Compound 33.

Thus, in some embodiments, Compound 33 Form K is substantially crystalline. In some embodiments, Compound 33 Fonn K. is substantially pure crystalline. In some embodiments, Compound 33 Fonn K is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation. FIG. 15A provides an Xray powder diffractogram of Compound Form K at room température.

In some embodiments, Compound 33 Form K is characterized by an X-ray powder diffractogram having a signal at 14.5 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Fonn K is characterized by an X-ray powder diffractogram having signais at 14.5 ± 0.2 degrees two-theta and at one or more of 9.7 ± 0.2 degrees two-theta, 19.7 ± 0.2 degrees twotheta, and 20.5 ±0.2 degrees two-theta. In some embodiments, Compound 33 Fonn K is characterized by an X-ray powder diffractogram having signais at 9.7 ± 0.2 degrees two-theta, 14.5 ± 0.2 degrees two-theta, 19.7 ± 0.2 degrees two-theta, and 20.5 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Form K is characterized b y an X-ray powder diffractogram having (a) signais at signais at 9.7 ± 0.2 degrees two-theta, 14.5 ± 0.2 degrees two-theta, 19.7 ± 0.2 degrees two-theta, and 20.5 ± 0.2 degrees two-theta, and a signal at at least one, at least two, at least three, at least four, at least five, or at least six, two-theta values chosen from 11.2 ± 0.2 degrees two-theta, 14.5 ± 0.2 degrees two-theta, 17.0 ± 0.2 degrees two-theta, 19.1 ± 0.2 degrees two-theta, 19.4 ± 0.2 degrees two-theta, 21.0 ± 0.2 degrees two-theta, and 24.4 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Fonn K is characterized by an X-ray powder diffractogram substantially similar to FIG. 15A.

Another aspect of the invention provides a composition comprising Compound 33 Form K. In some embodiments, the composition of the invention comprises substantially pure crystalline Compound 33 Form K. In some embodiments, the composition consists essentially of Compound 33 Form K.

Another aspect of the invention provides methods of making Compound 33 Form K. In some embodiments, Compound 33 Form K is prepared by dissolving Compound 33 Form A in 135

THF in a container, adding water, sealing the container, and storing at room temperature for enough time to allow the water vapor to interact with the solution, and isolating the precipitated solid.

16. Compound 33 2 Me-THF Solvaté Form A

In some embodiments, Compound 33 is a crystalline solid comprising of crystalline 2 Me-THF Solvaté Form A. In some embodiments, the crystalline solid comprises of 30% to 99% crystalline Compound 33 2 Me-THF Solvaté Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 40% to 99% Compound 33 2 Me-THF Solvaté Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 50% to 99% Compound 33 2 Me-THF Solvaté Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 60% to 99% Compound 33 2 Me-THF Solvaté Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 70% to 99% Compound 33 2 Me-THF Solvaté Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 75% to 99% Compound 33 2 MeTHF Solvaté Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 80% to 99% Compound 33 2 Me-THF Solvaté Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 85% to 99% Compound 33 2 Me-THF Solvaté Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 90% to 99% Compound 33 2 Me-THF Solvaté Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 95% to 99% Compound 33 2 Me-THF Solvaté Fonn A relative to the total weight of solid Compound 33.

Thus, in some embodiments, Compound 33 2 Me-THF Solvaté Fonn A is substantially crystalline. In some embodiments, Compound 33 2 Me-THF Solvaté Form A îs substantially pure crystalline. In some embodiments, Compound 33 2 Me-THF Solvaté Fonn A is characterized b y an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation. FIG. 16A provides an X-ray powder diffractogram of Compound 33 2 Me-THF Solvaté Fonn A at room temperature.

In some embodiments, Compound 33 2 Me-THF Solvaté Form A is characterized by an X-ray powder diffractogram having a signal at 18.1 ± 0.2 degrees two-theta, 19.0 ± 0.2 degrees two-theta, and/or 21.3 ± 0.2 degrees two-theta. In some embodiments, Compound 33 2 Me-THF Solvaté Fonn A is characterized by an X-ray powder diffractogram having (a) signais at 18.1 ± 0.2 degrees two-theta, 19.0 ± 0.2 degrees two-theta, and 21.3 ± 0.2 degrees two-theta; and (b) a signal at at least one, at least two, at least three, or at four two-theta values chosen from 13.8 ± 136

0.2 degrees two-theta, 18.7 ± 0.2 degrees two-theta, 20.0 ± 0.2 degrees two-theta, and 20.8 ± 0.2 degrees two-theta. In some embodiments, Compound 33 2 Me-THF Solvaté Form A is characterized by an X-ray powder diffractogram substantially similar to FIG. 16A.

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

Another aspect of the invention provides methods of making Compound 33 2 Me-THF Solvaté Form A. In some embodiments, Compound 33 2 Me-THF Solvaté Fonn A is prepared by dissolving Compound 33 Form A in 2 Me-THF, stirring the slurry for about two days at room température or one day at 5 °C, and isolating the solid form.

17. Compound 33 Fonn L

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

Thus, in some embodiments, Compound 33 Form L is substantially crystalline. In some embodiments, Compound 33 Fonn L is substantially pure crystalline. In some embodiments, Compound 33 Fonn L is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation. FIG. 17A provides an Xray powder diffractogram of Compound Form L at room température.

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Thus, in some embodiments, Compound 33 Fonn L is substantially crystalline. In some embodiments, Compound 33 Form L is substantially pure crystalline. In some embodiments, Compound 33 Form L is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu K a radiation. FIG. 17A provides an Xray powder diffractogram of Compound 33 Fonn L at room température.

In some embodiments, Compound 33 Fonn L is characterized by an X-ray powder diffractogram having signais at one or more of 14.5 ± 0.2 degrees two-theta, 14.6 ± 0.2 degrees two-theta, 16.3 ± 0.2 degrees two-theta, and 17.3 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Form L is characterized by an X-ray powder diffractogram having signais at 14.5 ± 0.2 degrees two-theta, I4.6 ± 0.2 degrees two-theta, 16.3 ± 0.2 degrees two-theta, and I7.3 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Fonn L is characterized by an Xray powder diffractogram having (a) signais at 14.5 ± 0.2 degrees two-theta, 14.6 ± 0.2 degrees two-theta, 16.3 ± 0.2 degrees two-theta, and 17.3 ± 0.2 degrees two-theta; and (b) a signal at at least one, at least two, at least four, at least six, at least eight, or at least ten two-theta values chosen from 7.0 ± 0.2 degrees two-theta, 8.8 ± 0.2 degrees two-theta, 9.9 ± 0.2 degrees twotheta, 13.7 ± 0.2 degrees two-theta, 17.6 ± 0.2 degrees two-theta, 17,9 ± 0.2 degrees two-theta, 18.6 ± 0.2 degrees two-theta, 18.8 ± 0.2 degrees two-theta, 19.7 ± 0.2 degrees two-theta, 20.2 ± 0.2 degrees two-theta, 20.4 ±0.2 degrees two-theta, 20.7 ± 0.2 degrees two-theta, 20.9 ± 0.2 degrees two-theta, 21.0 ± 0.2 degrees two-theta, 21.9 ± 0.2 degrees two-theta, 22.2 ± 0.2 degrees two-theta, 23.1 ± 0.2 degrees two-theta, 23.6 ± 0.2 degrees two-theta, 27.1 ± 0.2 degrees twotheta, 28.6 ± 0.2 degrees two-theta, and 31.7 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Form L is characterized by an X-ray powder diffractogram substantially similar to FIG. 17A

Another aspect of the invention provides a composition comprising Compound 33 Form L. In some embodiments, the composition of the invention comprises substantially pure crystalline Compound 33 Form L. In some embodiments, the composition consists essentially of Compound 33 Form L.

Another aspect of the invention provides methods of making Compound Fonn L. In some embodiments, Compound 33 Form L is prepared by dissolving Compound 33 Fonn A in 2MeTHF, allowing a slow évaporation at room température, and isolating the solid form. In some embodiments, Compound 33 Form L is prepared by adding Compound 33 Fonn A to 2McTHF/Heptane (1:1 by volume), heating and stirring the mixture at about 50 °C for about two hours until equilibrium is reached, filtering the mixture, slowly cooling to about 5 °C, and isolating the solid fonn.

18. Compound 33 Form M

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

Thus, în some embodiments, Compound 33 Form M is substantially crystalline. In some embodiments, Compound 33 Form M is substantially pure crystalline. In some embodiments, Compound 33 Form M is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation. FIG, I8A provides an Xray powder diffractogram of Compound 33 Form M at room température.

In some embodiments, Compound 33 Form M is characterized by an X-ray powder diffractogram having signais at one or more of 18.3 ± 0.2 degrees two-theta, 18.9 ± 0.2 degrees two-theta, and 21.2 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Form M is characterized by an X-ray powder diffractogram having signais at of 18.3 ± 0.2 degrees twotheta, 18.9 ± 0.2 degrees two-theta, and 21.2 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Form M is characterized by an X-ray powder diffractogram having (a) signais at of 18.3 ± 0.2 degrees two-theta, 18.9 ± 0.2 degrees two-theta, and 21.2 ± 0.2 degrees two-theta; and (b) a signal at at least one, at least two, at least three, or at least four two-theta values chosen from 7.0 ± 0.2 degrees two-theta, 8.4 ± 0.2 degrees two-theta, 11.3 ± 0.2 degrees two-theta, 13.8 ± 0.2 degrees two-theta, 16.0 ± 0.2 degrees two-theta, 17.2 ± 0.2 degrees two-theta, 9.4 ± 0.2 degrees two-theta, 20.6 ± 0.2 degrees two-theta, and 21.7 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Form M is characterized b y an X-ray powder diffractogram substantially similar to FIG. 18A.

139

Another aspect of the invention provides a composition comprising Compound 33 Fonn M. In some embodiments, the composition of the invention comprises substantially pure crystalline Compound 33 Form M. In some embodiments, the composition consists essentially of Compound 33 Form M.

Another aspect of the invention provides methods of making Compound 33 Form M. In some embodiments, Compound 33 Form M is prepared b y adding Compound 33 THF Solvaté Form A to methyl tert-butyl ether (MTBE) vapor in a container, sealing the container, storing at room température for about ten days, and isolating the solid form.

19. Compound 33 Form N

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

Thus, in some embodiments, Compound 33 Form N is substantially crystalline. In some embodiments, Compound 33 Fonn N is substantially pure crystalline. In some embodiments, Compound 33 Form N is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation. FIG. 19A provides an Xray powder diffractogram of Compound 33 Fonn N at room température.

In some embodiments, Compound 33 Form N is characterized by an X-ray powder diffractogram having signais at one or more of 13.0 ± 0.2 degrees two-theta, 14.3 ± 0.2 degrees two-theta, and 18.2 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Fonn N is characterized by an X-ray powder diffractogram having signais at 13.0 ± 0.2 degrees two-theta, 140

I4.3 ± 0.2 degrees two-theta, and 18.2 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Fonn N is characterized by an X-ray powder diffractogram having (a) signais at 13.0 ± 0.2 degrees two-theta, 14.3 ± 0.2 degrees two-theta, and 18.2 ± 0.2 degrees two-theta; and (b) a signal at at least two, at least four, at least six, at least eight, or at least ten two-theta values chosen from 4.2 ± 0.2 degrees two-theta, 8.8 ± 0.2 degrees two-theta, 11.7 ± 0.2 degrees twotheta, 12.3 ± 0.2 degrees two-theta, 12.6 ± 0.2 degrees two-theta, 15.6 ± 0.2 degrees two-theta, 17.1 ± 0.2 degrees two-theta, 17.6 ± 0.2 degrees two-theta, 18.7 ± 0.2 degrees two-theta, 19.2 ± 0.2 degrees two-theta, 19.6 ± 0.2 degrees two-theta, 20.5 ± 0.2 degrees two-theta, 21.5 ± 0.2 degrees two-theta, 21.8 ± 0.2 degrees two-theta, 22.2 ± 0.2 degrees two-theta, 22.7 ± 0.2 degrees two-theta, 23.1 ± 0.2 degrees two-theta, 24.0 ± 0.2 degrees two-theta, 25.6 ± 0.2 degrees twotheta, 26.1 ± 0.2 degrees two-theta, 26.8 ± 0.2 degrees two-theta, 28.0 ± 0.2 degrees two-theta, and 28.4 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Form N is characterized by an X-ray powder diffractogram substantially similar to FIG. 19A.

Another aspect of the invention provides a composition comprising Compound 33 Form N. In some embodiments, the composition of the invention comprises substantially pure crystalline Compound 33 Fonn N. In some embodiments, the composition consists essentially of Compound 33 Fonn N.

Another aspect of the invention provides methods of making Compound 33 Form N. In some embodiments, Compound 33 Form N is prepared by adding Compound 33 Fonn A to ethyl acetate (EtOAc), stirring ai room température, and isolating the solid form.

20. Compound 33 Form O

In some embodiments, Compound 33 is a crystalline solid comprising of Form O. In some embodiments, the crystalline solid comprises of 30% to 99% crystalline Compound 33 Fonn O relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 40% to 99% Compound 33 Form O relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 50% to 99% Compound 33 Form O relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 60% to 99% Compound 33 Form O relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 70% to 99% Compound 33 Form O relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 75% to 99% Compound 33 Form O relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 80% to 99% Compound 33 Form O relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 85% to 99% Compound 33 Form O relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 90% to 99% 141

Compound 33 Fonn O relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 95% to 99% Compound 33 Form O relative to the total weight of solid Compound 33.

Thus, in some embodiments, Compound 33 Fonn O is substantially crystalline. In some embodiments, Compound 33 Form O is substantially pure crystalline. In some embodiments, Compound 33 Form O is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation. FIG. 20A provides an Xray powder diffractogram of Compound 33 Form O at room température.

In some embodiments, Compound 33 Fonn O is characterized by an X-ray powder diffractogram having signais at one or more of 7.0 ± 0.2 degrees two-theta, 10.4 ± 0.2 degrees two-theta, 17.4 ± 0.2 degrees two-theta, and 21.2 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Fonn O is characterized by an X-ray powder diffractogram having signais at 7.0 ± 0.2 degrees two-theta, 10.4 ± 0.2 degrees two-theta, 17.4 ± 0.2 degrees two-theta, and 21.2 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Fonn O is characterized by an X-ray powder diffractogram having (a) diffractogram having signais at 7.0 ± 0.2 degrees two-theta, 10.4 ± 0.2 degrees two-theta, 17.4 ± 0.2 degrees two-theta, and 21,2 ± 0.2 degrees two-theta; and (b) a signal at at least one, at least two, at least four, or at least six two-theta values chosen from 8.3 ± 0.2 degrees two-theta, 8.8 ± 0.2 degrees two-theta, 15.5 ± 0.2 degrees two-theta, 16.6 ± 0.2 degrees two-theta, 16.9 ± 0.2 degrees two-theta, 18.8 ± 0.2 degrees two-theta, 19.5 ± 0.2 degrees two-theta, 20.4 ± 0.2 degrees two-theta, 21.6 ± 0.2 degrees two-theta, 22.3 ± 0.2 degrees twotheta, 22.9 ± 0.2 degrees two-theta, and 23.3 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Form O is characterized by an X-ray powder diffractogram substantially similar to FIG. 20A

Another aspect of the invention provides a composition comprising Compound 33 Fonn O. In some embodiments, the composition of the invention comprises substantially pure crystalline Compound 33 Form O. In some embodiments, the composition consists essentîally of Compound 33 Form O.

Another aspect of the invention provides methods of making Compound 33 Form O. In some embodiments, Compound 33 Form O îs prepared by suspending Compound 33 THF Solvaté Form A in ethyl acetate (EtOAc), stirring the suspension at room température for about two days, and isolating the solid form.

21. Compound 33 Potassium Sait Form A

In some embodiments, Compound 33 is a crystalline solid comprising of Potassium Sait Form A. In some embodiments, the crystalline solid comprises of 30% to 99% crystalline Compound 33 Potassium Sait Form A relative to the total weight of solid Compound 33. In 142 some embodiments, the crystalline solid comprises of 40% to 99% Compound 33 Potassium Sait Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 50% to 99% Compound 33 Potassium Sait Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 60% to 99% Compound 33 Potassium Sait Fonn A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 70% to 99% Compound 33 Potassium Sait Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 75% to 99% Compound 33 Potassium Sait Fonn A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 80% to 99% Compound 33 Potassium Sait Form A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 85% to 99% Compound 33 Potassium Sait Fonn A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 90% to 99% Compound 33 Potassium Sait Fonn A relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 95% to 99% Compound 33 Potassium Sali Fonn A relative to the total weight of solid Compound 33.

Thus, in some embodiments, Compound 33 Potassium Sait Form A is substantially crystalline. In some embodiments, Compound 33 Potassium Sait Form A is substantially pure crystalline. In some embodiments, Compound 33 Potassium Sait Fonn A is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation. FIG. 21A provides an X-ray powder diffractogram of Compound 33 Potassium Sait Form A at room température.

In some embodiments, Compound 33 Potassium Sait Form A is characterized by an Xray powder diffractogram having signais at one or more of 11.7 ± 0.2 degrees two-theta, 18.0 ± 0.2 degrees two-theta, and 20.7 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Potassium Sait Fonn A is characterized by an X-ray powder diffractogram having signais at 11.7 ±0.2 degrees two-theta, 18.0 ± 0.2 degrees two-theta, and 20.7 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Potassium Sait Fonn A is characterized by an X-ray powder diffractogram substantially similar to FIG. 21A.

Another aspect of the invention provides a composition comprising Compound 33 Potassium Sait Fonn A. In some embodiments, the composition of the invention comprises substantially pure crystalline Compound 33 Potassium Sait Fonn A. In some embodiments, the composition consists essentially of Compound 33 Potassium Sait Form A.

Another aspect of the invention provides methods of making Compound 33 Potassium Sait Fonn A. In some embodiments, Compound 33 Potassium Sait Fonn A is prepared by dissolving Compound 33 Form A into acetone at about 50 °C, dispensing the Compound 33

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Form A acetone solution into a container at room température, adding KOH aqueous solution, and obtaining Compound 33 Potassium Sait Form A via évaporation at room température.

22. Compound 33 Potassium Sait Form B

In some embodiments, Compound 33 is a crystalline solid comprising of Potassium Sait Fonn B. In some embodiments, the crystalline solid comprises of 30% to 99% crystalline Compound 33 Potassium Sait Fonn B relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 40% to 99% Compound 33 Potassium Sait Fonn B relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 50% to 99% Compound 33 Potassium Sait Form B relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 60% to 99% Compound 33 Potassium Sait Fonn B relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 70% to 99% Compound 33 Potassium Sait Fonn B relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 75% to 99% Compound 33 Potassium Sait Fonn B relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 80% to 99% Compound 33 Potassium Sait Form B relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 85% to 99% Compound 33 Potassium Sait Fonn B relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 90% to 99% Compound 33 Potassium Sait Form B relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 95% to 99% Compound 33 Potassium Sait Fonn B relative to the total weight of solid Compound 33.

Thus, in some embodiments, Compound 33 Potassium Sait Fonn B is substantially crystalline. In some embodiments, Compound 33 Potassium Sait Form B is substantially pure crystalline. In some embodiments, Compound 33 Potassium Sait Fonn B is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ko radiation. FIG. 22A provides an X-ray powder diffractogram of Compound 33 Form B at room température.

In some embodiments, Compound 33 Potassium Sait Form B is characterized by an Xray powder diffractogram having signais at one or more of 9.1 ± 0.2 degrees two-theta, 13.7 ± 0.2 degrees two-theta, 15.3 ± 0.2 degrees two-theta, 17.5 ± 0.2 degrees two-theta, and 21.7 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Potassium Sait Form B is characterized by an X-ray powder diffractogram having signais at two or more of 9.1 ± 0.2 degrees two-theta, 13.7 ± 0.2 degrees two-theta, 15.3 ± 0.2 degrees two-theta, 17.5 ± 0.2 degrees two-theta, and 21.7 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Potassium Sait Fonn B is characterized by an X-ray powder diffractogram having signais at three or more of 9.1 ±0.2 144 degrees two-theta, 13.7 ± 0.2 degrees two-theta, 15.3 ± 0.2 degrees two-theta, 17.5 ± 0.2 degrees two-theta, and 21.7 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Potassium Sait Form B is characterized by an X-ray powder diffractogram having signais at 9.1 ± 0.2 degrees two-theta, 13.7 ± 0.2 degrees two-theta, 15.3 ± 0.2 degrees two-theta, 17.5 ± 0.2 degrees two-theta, and 21,7 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Potassium Sait Fonn B is characterized b y an X-ray powder diffractogram having (a) signais at three or more of 9.1 ± 0.2 degrees two-theta, 13.7 ± 0.2 degrees two-theta, 15.3 ± 0.2 degrees two-theta, ] 7.5 ± 0.2 degrees two-theta, and 21.7 ± 0.2 degrees two-theta; and (b) a signal at at least one, at least two, or at least three two-theta values chosen from 6.9 ± 0.2 degrees two-theta, 10.8 ± 0.2 degrees two-theta, 20.0 ± 0.2 degrees two-theta, and 20.6 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Potassium Sait Form B is characterized by an X-ray powder diffractogram substantially similar to FïG. 22A.

Another aspect of the invention provides a composition comprising Compound 33 Potassium Sait Form B. In some embodiments, the composition of the invention comprises substantially pure crystalline Compound 33 Potassium Sait Form B. In some embodiments, the composition consists essentially of Compound 33 Potassium Sait Fonn B.

Another aspect of the invention provides methods of making Compound 33 Potassium Sait Form B. In some embodiments, Compound 33 Potassium Sait Fonn B is prepared by dissolving Compound 33 Fonn A into 1,4-dioxane at about 50 °C with sonication, dispensing the Compound 33 1,4-dioxane solution into a container at room température, adding KOH aqueous solution, and isolating Compound 33 Potassium Sait Form B at room température.

23. Compound 33 Potassium Sait Fonn C

In some embodiments, Compound 33 is a crystalline solid comprising of Potassium Sait Fonn C. in some embodiments, the crystalline solid comprises of 30% to 99% crystalline Compound 33 Potassium Sait Form C relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 40% to 99% Compound 33 Potassium Sait Fonn C relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 50% to 99% Compound 33 Potassium Sait Form C relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 60% to 99% Compound 33 Potassium Sait Form C relative to the total weight of solid Compound 33, In some embodiments, the crystalline solid comprises of 70% to 99% Compound 33 Potassium Sait Form C relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 75% to 99% Compound 33 Potassium Sait Form C relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 80% to 99% Compound 33 Potassium Sait Form C relative to the total weight of solid Compound 33. In 145 some embodiments, the crystalline solid comprises of 85% to 99% Compound 33 Potassium Sait Form C relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 90% to 99% Compound 33 Potassium Sait Form C relative to the total weight of solid Compound 33. In some embodiments, the crystalline solid comprises of 95% to 99% Compound 33 Potassium Sait Form C relative to the total weight of solid Compound 33.

Thus, in some embodiments, Compound 33 Potassium Sait Form C is substantially crystalline. In some embodiments, Compound 33 Potassium Sait Fonn C is substantially pure crystalline. In some embodiments, Compound 33 Potassium Sait Fonn C is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ko radiation. FIG, 23A provides an X-ray powder diffractogram of Compound 33 Potassium Sait Fonn C at room temperature.

In some embodiments, Compound 33 Potassium Sait Fonn C is characterized by an Xray powder diffractogram having signais at 16.8 ± 0.2 degrees two-theta and 19.3 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Potassium Sait Form C is characterized by an X-ray powder diffractogram having signais at (a) 16.8 ± 0.2 degrees two-theta and 19.3 ± 0.2 degrees two-theta and (b) 6.7 ± 0.2 degrees two-theta, and/or 10.5 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Potassium Sait Form C is characterized by an X-ray powder diffractogram having a signal at 6.7 ± 0.2 degrees two-theta, 10.5 ± 0.2 degrees two-theta. 16.8 ± 0.2 degrees two-theta, and 19.3 ± 0.2 degrees two-theta. In some embodiments, Compound 33 Potassium Sait Fonn C is characterized by an X-ray powder diffractogram substantially similar to FIG. 23A.

Another aspect of the invention provides a composition comprising Compound 33 Potassium Sait Form C. In some embodiments, the composition of the invention comprises substantially pure crystalline Compound 33 Potassium Sait Fonn C. In some embodiments, the composition consists essentially of Compound 33 Potassium Sait Fonn C.

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

Solid Dispersions Comprising Amorphous Compound 33

In another aspect, the invention features a solid dispersion comprising the amorphous Compound 33 and a polymer. In one embodiment, the polymer is hydroxypropylmethylcellulose 146 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 WO 2011/119984, which is incorporated herein by reference in its entirety.

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

In another embodiment, Compound 33 is present în an amount from about 30% by weight 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.

Some embodiments provide spray dried neat amorphous Compound 33 without polymer.

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 spray-dried, neat substantially amorphous Compound 33 without polymer.

Methods of Preparing Amorphous Compound and Solid Dispersions

Amorphous forms of any of the compounds disclosed herein and solid dispersions comprising those amorphous compounds can be prepared. Starting from a compound of the invention or a sait, solvaté or hydrate of that compound, the amorphous form of of the compound may be prepared b y rotary évaporation or by spray dry methods. In some embodiments, the amorphous Compound of the invention is Compound 33 or a pharmaceutically acceptable sait or deuterated derivatîve thereof. Some embodiments of the invention provide a pharmaceutical composition comprising amorphous Compound 33 or a pharmaceutically acceptable sait or deuterated dérivative thereof. In some embodiments, the composition comprising amorphous Compound 33 or a pharmaceutically acceptable sait or deuterated dérivative thereof is a spraydried dispersion.

Dissolving a compound, a sait, solvaté or hydrate of the invention in an appropriate solvent like methanol and rotary evaporating the methanol to leave a foam produces the amorphous fonn. In some embodiments, a warm water bath is used to expedite the évaporation.

Amorphous form may also be prepared from any of the compounds, salts, solvatés or hydrates described herein, including, e.g., Compound 33 and salts, solvatés and hydrates of 147

Compound 33, using spray dry methods. Spray drying is a process that converts a liquid feed to a dried particulate form. Optionally, a secondary drying process such as fluidized bed drying or vacuum drying, may be used to reduce residual solvents to pharmaceutically acceptable levels. Typically, spray drying involves contacting a highly dispersed liquid suspension or solution, and a sufficient volume of hot air to produce évaporation and drying of the liquid droplets. The préparation to be spray dried can be any solution, coarse suspension, slurry, colloïdal dispersion, or paste that may be atomized using the selected spray drying apparatus. In a standard procedure, the préparation is sprayed into a current of warm filtered air that evaporates the solvent and conveys the dried product to a collector (e.g. a cyclone). The spent air is then exhaustcd with the solvent, or altematively the spent air is sent to a condenser to capture and potentially recycle the solvent. Commercially available types of apparatus may be used to conduct the spray drying. For ex ample, commercial spray dryers are manufactured by Buchi Ltd. And Niro (e.g., the PSD line of spray driers manufactured by Niro) (see, US 2004/0105820; us 2003/0144257).

Spray drying typically employs solid loads of material from about 3% to about 30% by weight, (i.e., drug and excipients), for example about 4% to about 20% by weight, preferably at least about 10%. In general, the upper limit of solid loads is govemed by the viscosity of ( e.g., the ability to pump) the resulting solution and the solubility of the components in the solution. Generally, the viscosity of the solution can detennine the size of the particle in the resulting powder product.

Techniques and methods for spray drying may be found în Perry's Chemical Engineering Handbook, 6th Ed., R.H. Perry, D. W. Green & J. 0. Maloney, eds.), McGraw-Hill book co. (1984); and Marshall Atomizatîon and Spray-Drying 50, Chem. Eng. Prog. Monogr. Sériés 2 (1954). In general, the spray drying is conducted with an inlet température of from about 60 °C to about 200 °C, for example, from about 95 °C to about 185 °C, from about 110 °C to about 182 °C, from about 96 °C to about 180 °C, e.g., about 145 °C. The spray drying is generally conducted with an outlet température of from about 30 °C to about 90 °C, for example from about 40 °C to about 80 °C, about 45 °C to about 80 °C e.g., about 75 °C. Theatomization flow rate is generally from about 4 kg/h to about 12 kg/h, for example, from 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 from about 3 kg^zh to about 10 kg/h, for example, from about 3.5 kg/h to about 9.0 kg/h, e.g., about 8 kg/h or about 7.1 kg/h. The atomizatîon ratio îs generally from about 0.3 to 1.7, e.g., from about 0.5 to 1.5, e.g., about 0.8 or about 1.5.

Removal of the solvent may require a subséquent drying step, such as tray drying, fluid bed drying ( e.g., from about room température to about 100 °C), vacuum drying, microwave

148 drying, rotary drum drying or biconical vacuum drying (e.g,, from about room température to about 200 °C).

In another aspect, the invention features a process of preparing amorphous Compound 33 comprising spray drying the compound. In another embodiment, the process comprises combining Compound 33 (or a sait, solvaté, or hydrate thereof) and a suitabie solvent or a mixture of solvents and then spray drying the mixture to obtain amorphous Compound 33. In another embodiment, the solvent is an organic solvent or a mixture of organic solvents. In another embodiment, the solvent is an organic solvent or a mixture of organic solvents selected from dichloromethane (DCM), éthanol (EtOH), tetrahydrofuran (THF), and 2methyltetrahydrofuran (Me-THF). In another embodiment, the mixture of solvents comprises one or more organic solvents in combination with water, such as about l% 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 suitabie exemplary solvents are as described in WO 2011/119984, which is incorporated herein by reference in its entirety.

In another embodiment, the process comprises: a) forming a mixture comprising Compound 33 (or a sait, solvaté, or hydrate thereof), a polymer, and a solvent or a mixture of solvents; and b) spray drying the mixture to fonn a solid dispersion.

Another aspect of the invention provides pharmaceutical compositions comprising a compound according to any one formula chosen from Fonnulae I, I-A, I-B, I-C, I-D, I-E, I-F, I-G, and I-H and Compounds 1-342, tautomers of those compounds, phannaceutically acceptable salts of those compounds and their tautomers, and deuterated derivatives of any of the foregoing. In some embodiments, the pharmaceutical composition comprising at least one compound chosen from Fonnulae I, I-A, I-B, I-C, I-D, I-E, I-F, I-G, and I-H and Compounds 1-342, tautomers of those compounds, phannaceutically acceptable salts of those compounds and their tautomers, and deuterated derivatives of any of the foregoing is administered to a patient in need thereof.

A pharmaceutical composition may further comprise at least one phannaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is chosen from phannaceutically acceptable vehicles and phannaceutically acceptable adjuvants.

149

In some embodiments, the at least one phannaceuticai l y acceptable is chosen from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, lubricants.

It will also be appreciated that a pharmaceutical composition of this disclosure can be employed in combination thérapies; that is, the pharmaceutical compositions described herein can further include another active therapeutic agent. Altematively, a phannaceuticai composition comprising at least one compound of Formulae I, I-A, I-B, Ï-C, 1-1), I-E, I-F, 1-G, and I-1I and tautomers of those compounds, phannaceutically acceptable salts of those compounds and their tautomers, and deuterated dérivatives of any of the foregoing can be administered as a separate composition concurrently with, prior to, or subséquent to, a composition comprising at least one other active therapeutic agent. In spécifie embodiments, a pharmaceutical composition comprising at least one compound selected from Compounds 1-342 tautomers of those compounds, pharmaceutically acceptable salts of those compounds and their tautomers, and deuterated dérivatives of any of the foregoing can be administered as a separate composition concurrently with, prior to, or subséquent to, a composition comprising at least one other active therapeutic agent.

As described above, phannaceuticai compositions disclosed herein may optionally further comprise at least one phannaceutically acceptable carrier. The at least one phannaceutically acceptable carrier may be chosen from adjuvants and vehicles. The at least one pharmaceutically acceptable carrier, as used herein, includes any and ali solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surface active agents, isotonie agents, thickening agents, emulsifying agents, preservatives, solid binders, and lubricants, as suited to the particular dosage form desired. Remington: The Science and Practice of Pharmacy, 21 st édition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York discloses various carriers used in formulating phannaceuticai compositions and known techniques for the préparation thereof. Except insofar as any conventionai carrier is incompatible with the compounds of this disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this disclosure. Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stéarate, lecithin, sérum proteins (such as human sérum 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), colloïdal silica, magnésium trisilicate, polyvinyl 150 pyrrotidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as lactose, glucose and sucrose), starches (such as corn starch and potato starch), cellulose and its dérivatives (such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), 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, buffering agents (such as magnésium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonie saline, Ringer's solution, ethyl alcohol, phosphate buffer solutions, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnésium stearate), colonng agents, releasing agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservatives, and antioxidants.

In another aspect of the invention, the compounds and the pharmaceutical compositions, described herein, are used to treat AATD. In some embodiments, the subject in need of treatment with the compounds and compositions of the invention cames the ZZ mutation. In some embodiments, the subject in need of treatment with the compounds and compositions of the invention carries the SZ mutation.

In some embodiments, the methods of the invention comprise administering to a patient in need thereof at least one compound chosen from any of the compounds of Formulae I, I-A, IB, I-C, I-D, I-E, I-F, I-G, and I-H and tautomers of those compounds, pharmaceutically acceptable salts of those compounds and their tautomers, and deuterated dérivatives of any of the foregoing. In some embodiments, the compound of Formula T is selected from Compounds 1-342, tautomers of those compounds, pharmaceutically acceptable salts of those compounds and their tautomers, and deuterated dérivatives of any of the foregoing. In some embodiments, said patient in need thereof has a Z mutation in the alpha-1 antitrypsin gene. In some embodiments said patient in need thereof is homozygous for the Z-mutation in the alpha-1 antitrypsin gene.

Another aspect of the invention provides methods of modulating alpha-1 antitrypsin activity comprising the step of contacting said alpha-1-antitrypsin with at least one compound of Formulae I, I-A, I-B, I-C, I-D, I-E, I-F, I-G, and I-II and tautomers of those compounds, pharmaceutically acceptable salts of those compounds and their tautomers, and deuterated dérivatives of any of the foregoing. In spécifie embodiments, the methods of modulating alpha-1 antitrypsin activity comprising the step of contacting said alpha-1 -antitrypsin with at least one compound selected from Compounds 1-342, tautomers of those compounds, pharmaceutically acceptable salts of those compounds and their tautomers, and deuterated dérivatives of any of the foregoing.

151

Some embodiments of the invention provide spray-dried dispersions of compounds of the invention, pharmaceutically acceptable salts, and deuterated derivatives thereof. In some embodiments, the spray-dried dispersion comprises 30-50% Compound 33 (or a sait, or deuterated dérivative thereof) and a polymer. In some embodiments, the spray-dried dispersion comprises 30-50% Compound 33 (or a sait or deuterated dérivative thereof) and polyvinylpyiTolidone/vinyl acetate (PVPVA). In some embodiments, the spray-dried dispersion comprises 30-50% Compound 33 (or a sait or deuterated dérivative thereof) and hydroxypropylmethylcellulose (HPMC). In some embodiments, the spray-dried dispersion comprises 30-50% Compound 33 (or a sait or deuterated dérivative thereof) and HPMCAS. In some embodiments, the spray-dried dispersion comprises 50-80% Compound 33 (or a sait or deuterated derivatîve thereof) and a polymer. In some embodiments, the spray-dried dispersion comprises 50-80% Compound 33 (or a sait or deuterated derivatîve thereof) and polyvinylpyrrolidone/vinyl acetate (PVPVA). In some embodiments, the spray-dried dispersion comprises 50-80% Compound 33 (or a sait or deuterated derivatîve thereof) and hydroxypropylmethylcellulose (HPMC). In some embodiments, the spray-dried dispersion comprises 50-80% Compound 33 (or a sait or deuterated derivatîve thereof) and HPMCAS.

III. Préparation of Compounds

Ail the generic, subgeneric, and spécifie compound fonnulae disclosed herein are considered part of the invention.

A. Compounds of Formula I

The compounds of the invention may be made according to standard Chemical practices or as described herein. Throughout the following synthetic schemes and in the descriptions for preparing compounds of Formulae I, I-A, I-B, I-C, I-D, I-E, I-F, I-G, and III, 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:

Abbreviations

I8-crown-6 = 1,4,7,10,13,16-hexaoxacyclooctadecane

BrettPhos Pd G1 = chloro[2-(dicyclohexylphosphmo)-3,6-dimethoxy-2',4', 6'-triisopropyl-l,l'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-2yl)phenyl]phenyl]phosphane;methanesulfonic acid;N-methyI-2-phenylaniIine;palladium

152

CBzCl = benzyl chlorofonnate

Cphos = 2-dicyclohexy]phosphino-2'_f6'-bis(N_;N-dimethylamino)biphenyl

Cs₂CO₃ = césium carbonate

DCE = l,2-dichloroethane

DIPEA = Ν,Ν-diisopropyl ethyl amine or N-ethyl-N'isopropyl-propan-2-amine

DMAP = dimethylamino pyridine

DMF = dimethylfonnamide

DMSO = dîmethyl sulfoxide

Dppf = l, l '-ferrocenediyl-bis(diphenylphosphine)

DTBPF = l,l '-bis(di-tert-buty]phosphino)ferrocene

EtOAc = ethyl acetate

HATU = [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium (Phosphorus Hexafluoride Ion)

IPA = isopropyl alcohol

KOzBu = potassium ierz-butoxîde

K3PO4 = potassium phosphate tribasic

MeOH = methanol

MP-TMT scavenger resin = a macroporous polystyrene-bound trimercaptotriazine, a resin bound équivalent of 2,4,6-triinercaptotrîazine (TMT).

MTBE = methyl te/7-butyl ether

NaCNBH₃ = sodium cyanoborohydride

NMM = N-methyl morpholîne

NaOiBu = sodium zerz-butoxide

Pd₂(dba)₃ = tris(dibenzylideneacetone)dipalladium (0)

Pd(dppf)2Cl₂ = [1,1 '“Bis(diphenylphosphino)fenOcene]dichloropalIadium(II)

PdCl₂(PPh₃)₂ = bis(triphenylphosphine)palladium(n) dichloride

Pd(OAc)2 = palladium(II) acetate

Pd(zBu3P)₂ = bis(tri-to'Abutylphosphme)palladium(O)

PivCl = pivaloyl chloride

PTS A = p-toluenesulfonic acid monohydrate rac-BINAP = (±)-2,2'-bis(diphenylphosphino)-l_ïl'-binaphthalene

[Rh(COD)Cl]2 = chloro(l,5-cyclooctadiene)rhodium (I) dimer

SEMCl = 2-(trimethylsilyl)ethoxymethyl chloride

SFC = super critical fluid chromatography

SPhos = 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl

153

SPhos Pd G4 = dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphane;methanesulfonic acid;N-methyI-2-phenylaniline;palladîum

SPM32 = 3-mercaptopropyl ethyl sulfide Silica

TBAB = tetrabutylammonium bromide

TBAF = tetrabutylammonium fluoride tBuXPhos Pd Gl = chloro[2-(di-zei7-butylphosphiiio)-2',4',6'-triisopropyl-l,l'-biphenyl][2-(2aminoethyl)phenyl)|palladium(II) or /-BuXPhos palladium(II) phenethylamine chloride tBuXPhos Pd G3 = [(2-di-terAbutylphosphmü-2',4'₅6'-triisopropyl-1, l '-biphenyi)-2-(2'-aminol, l '-biphenyl)] palladium(II) méthanesulfonate tBuXPhos Pd G4 = methanesulfonato(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-l,l'biphenyl)(2'-methylamino-l,r-biphenyl-2-yl)palladium(n) 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-l ,1'biphenyl)]palladium(n) methanesulfonate

XPhos Pd Gl = (2-dicyclohexyIphosphmo-2',4',6'-triisopropyl-i,l'-biphenyl)[2-(2aminoethyl)phenyl)]paHadium(II) chloride or (XPhos) palladium(II) phenethylamine chloride

XPhos Pd G3 = (2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyI)[2-(2'-amino-l,rbiphenyl)]palladium(II) methanesulfonate

In some embodiments, processes for preparing compounds of Formula I, tautomers, pharmaceutically acceptable salts of those compounds or tautomers, or deuterated derivatives of any of the foregoing, comprise reactions depicted in Schemes 1-9 below:

Scheme 1 provides methods for préparation of compounds of Formula I, tautomers, salts or derivatives thereof, from a compound of Formula 1-1, wherein variables X¹, X² R°, R¹, R², R³, Z¹, Z², Z³, and n are defined as above in Formula I. When at least one of Z¹, Z², or Z³ is a nitrogen atom, a protecting group (PG¹) is used. In some embodiments, PG¹ is chosen from ptoluenesulfonamide (Tosyl), pivaloyl (Piv), trimethylsilyl ethoxymethyl (SEM), tetrahydropyranyl (THP), phenyl sulfonyl, benzyl carbamate (Cbz), Benzyl (Bn), pmethoxybenzyl (PMB), t-butyl carbamate (Boc), allyloxycarbamate (Alioc), 9-fluorenylmethyl carbamate (FMOC), methoxymethyl (MOM), Benzyloxymethyl (BOM), 2-methoxyethoxyethyl (MEM), trifluoroacetamide or any other suitable protecting group. Any suitable conditions 154 known in the art, such as those for a deprotection reaction of a nitrogen atom, can be used for préparation of compounds of Formula I from compounds of Formula 1-1. In some embodiments, the reaction depîcted în scheme 1 is performed in the presence of a base, such as a métal hydroxide (e.g. an aqueous solution of NaOH or KOH). The reaction may be performed at elevated température (e.g. 60 °C). A solvent mixture such as MeOH and THF may be used. Alternative conditions known in the art may be used as appropriate for the deprotection of PG¹. Scheme 1

In some embodiments, as shown in Scheme 2, processes for the préparation of compounds of Fonnula 1-1, comprise reacting a compound of Fonnula 2-1, (wherein X¹, X² R°, 1 ^3123

R , R“, R , Z, Z^z, Z\ andn are defined as above in Fonnula I.), with a boronic acid or ester of Formula 2-3, a boronic ester of fonnula 2-4, or a boronic ester of formula 2-5, R¹¹ may be hydrogen, or a suitable alkyl such as Me, Et, propyl, isopropyl, or isobutyl. Each R¹² may independently be hydrogen, methyl, or any other suitable alkyl group. X³ is any suitable halide (e.g. I, Br or Cl). Variable p may be 1 or 2. In some embodiments, the reactions generating a compound 1-1 are perfonned in the presence of any suitable coupling reagent, such as palladium a catalyst (e.g. Pd(dppf)C12, Pd(OAc)₂, PdfPPhjfy or XPhos Pd G3) in the presence of a base (Na₂COj, Cs₂CO₃, K3PO4). In some embodiments, the reaction may be performed in a polar solvent (1,4-dioxane) in the presence of added heat (>80 °C).

Scheme 2

Scheme 3 refers to an additional process for the préparation of compounds of Formula 11 from compounds of Fonnula 2-1 wherein, variables depicted in scheme 3 are defined as above.

155

R^b is a hydrogen aiom or any suitable alkyl group (e.g. Me, Et). X⁴ îs any suitable halogen (e.g. I, Br, or Cl). A compound of Formula 3-1 may be prepared from a compound of Formula 2-1 using any suitable conditions for formation of a boronate ester from an aryl halide. In some embodiments, 4,4,5,5-tetramethyl-l,3,2-dioxaborolane in the presence of a catalyst (e.g. Pd(dppf)C12) and an organic base (triethylamine) may be used. A compound of Formula 3-1 may be converted to compound of Formula 1-1 via a cross-coupling reaction with a halide of Formula 3-2, in the presence of a suitable catalyst and base. For example, in some embodiments, the coupling reaction is performed in the presence of a catalyst such as Pd(dppf)Cb, base (e.g. Na₂CO₃). The reaction may be performed in polar solvent (1,4-dioxane), at elevated temperature (e.g. >90 °C).

Scheme 3

1-1

Scheme 4 provides processed for the préparation of compounds of Formula 2-1. X⁵ and X⁶ are any suitable halogen (e.g. Cl, Br or I). E¹ is hydrogen, SiMe₃ or SnBu₄. Ail other variables are defined as above. Compounds of Formula 2-1 may be used in scheme 2 and scheme 3 above. Any suitable conditions, for alkyne coupling known in the art (e.g. Sonagashira coupling) may be used to préparé a compound of Formula 4-3 from a compound of Formula 2-1 and alkynes of Formula 4-2. In some embodiments, the reaction may be performed în the presence of Cul and PdfPPhshCb. In some embodiments, a base such as triethylamine or DIPEA may be used. In some additional embodiments, KOH or CsF may be present. Compounds of Formula 4-3 and amines of Formula 4-4 may 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 perfonned in the presence of a catalyst (e.g. BrettPhos Pd Gl, tBuXPhos Pd Gl, BrettPhos Pd

156

G4 or tBuXPhos Pd Gl). The réaction may be performed in the presence of a suitable base (e.g. NaOtBu), and a solvent such as THF, tBuOH or éthanol. In some embodiments the reaction may be performed with added heat (70 °C). A compound of Formula 4-5 may be converted to a compound of Formula 4-6 using any suitable condition for the întramolecular reaction of an amine with an alkyne. The reaction may be performed in the presence of a polar solvent (DMSO, EtOH or AcOH) with added heat (e.g. 60 ^ÛC or 150 °C). In some embodiments, the reaction is performed in the presence of Cul. Any suitable condition known to those skilied in the art, such as those used for the protection of a nitrogen atom, may be used to générale a compound of Formula 4-7 from compounds of Fonnula 4-6. In some embodiments, the reaction is performed in the presence of pivaloyl chloride (Piv-Cl) or p-toluenesulfonyl chloride (Ts-Cl). The reaction may be performed in the présences of a base (e.g. KOtBu). A suitable halogenating agent (e.g. N-iodosuccinimide) may be used in the conversion of a compound of Formula 4-7 to a compound of Formula 2-1.

Scheme 4

4-7 2-1

Scheme 5 provides processes for preparing compounds of Formula 5-6 from compounds of Fonnula 5-1. X⁷ is any suitable halogen (e.g. Cl, Br or I). X⁸ is a suitable halogen (e.g. Cl, Br or I). Other variables are defined as in Formula L Compounds of Formula 5-6 may be used as a compound of Fonnula 1-1 in scheme 1. A compound of Fonnula 5-3 may be prepared by 157 reacting a compound of Formula 5-1 and a compound of Formula 5-2. The réaction may be performed în the presence of a catalyst system (e.g. tBuXPhos Pd G4) and a base (e.g. NaOtBu). The reaction may be performed in a solvent such as tBuOH. Compounds of Formula 5-4 may be prepared from compounds of Formula 5-3 using any reagent appropriate for the protection of a nitrogen atom. In some embodiments, pivaloyl chloride (Piv-Cl) în the presence of a base (e.g. KOtBu) may be used. Compounds of Formula 5-6 may be prepared by reacting compounds of Formula 5-4 with alkynes of Formula 5-5 in the presence of a catalyst (e.g. Pd(P_tBuj)2) and an amine base (e.g. iV-methyldicyclohexylamine). In some embodiments, the reaction may be performed in a polar solvent such as 1,4-dioxane, with added heat (110 °C).

Scheme 5

5-1

R°

5-⁴ 5-6

Scheme 6 depicts processes for the préparation of compounds of Formula 6-8. Compounds of Formula 6-8 may be used as a compound of Formula 2-1 above. X⁹ and X¹⁰ are independently selected halogens (e.g. Cl, Br, or I). X¹¹ is a halogen (e.g. Br or I). E³ is a hydrogen atom, SnBu₄ or SiMej. Ail other variables are as defined in Formula I.

Compounds of Formula 6-1 may be coupled to alkynes of Formula 6-2 using any suitable conditions for aryl halide to alkyne coupling known to those skilled in the art (e.g. Sonagashira coupling). In some embodiments, the reaction may be performed in the presence of Cul and PdæPhj^Cb. In some embodiments, a base such as triethylamine or DIPEA may be used. In some alternative embodiments, bases such as KOH or CsF may be used. Any suitable condition, such as those for performing amination reactions may be used to react compounds of Formula 63 and amines of Formula 6-4 to give a compound of Formula 6-5. For example, the reaction may be performed in the presence of a catalyst (e.g. BrettPhos Pd Gl, tBuXPhos Pd Gl, BrettPhos Pd G4 or tBuXPhos Pd Gl), a suitable base (e.g. NaOtBu), and a solvent such as THF, tBuOH or

158 éthanol. In some embodiments the reaction may be performed with added heat (70 °C). Compounds of Formula 6-6 may be prepared from compounds of Formula 6-5 using any suitable condition for the intramolecular addition of an amine to an alkyne. In some embodiments, the reaction may be performed by heating a compound of Formula 6-5 in a suitable solvent (e.g.

DMSO at 150 °C). In an alternative embodiment, compounds of Fonnula 6-5 may be heated (60 °C) în a solvent such as EtOH, in the presence of AcOH. Compounds of Fonnula 6-7 may be prepared from 6-6 using a suitable protecting group reagent. For example, PivCI, SEM-C1 or PhSO2-Cl may be used. The reaction may be performed in the presence of any suitable base (e.g. KOtBu or KOH). Compounds of Formula 6-8 may be prepared by reaction of compounds of

Fonnula 6-7 with a halogenatmg agent (e.g N-iodosuccinimide or N-bromosuccinimide) in a solvent such as dichloromethane.

Scheme 6

Scheme 7 provides processes for préparation of compounds of Formula 7-3. X¹¹ is a suitable halide (e.g. Cl, Br, 1). R¹⁴ îs a hydrogen atom, or any suitable alkyl group (e.g. Me or Et). R¹⁴ groups may also be linked through a single carbon-carbon bond to form a cyclic boronate ester, R¹⁵ is any suitable alkyl (e.g. Me or Et). Ar is any suitable 5 or 6 membered

159 aromatic group, such that a compound of Fonnula 7-3 may be also a compound of Formula I. Any suitabie condition known to those in the art may be used for coupling of a compound of Formula 6-8 with a boronic acid or boronic ester of Fonnula 7-1. In some embodiments, the coupling reaction is perfonned 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. Na₂CCh or K3PO4). The reaction may be perfonned in polar solvent (1,4-dioxane or DMF), at elevated température (e.g. 70 °C). Any suitabie reagents known in the art, such as those suitabie for the hydrolysis of an ester and appropriate for removal of a protecting group PG¹ from a nitrogen atom, may be used to préparé compounds of Formula 7-3 from compounds of Formula 7-2. In some embodiments, an aqueous solution of base (e.g. NaOH or KOH) in a polar solvent (e.g. a THF and MeOH mixture) may be used. The reaction may be performed with added heat (e.g. 55 °C). In alternative embodiments, the reaction may be performed in the presence of an amine (e.g. piperidine).

Scheme 7

Scheme S shows an alternative process for the préparation of compounds of Formula 7-3 from 6-8. X¹¹ is a suitabie halide (e.g. CI, Br, I). R¹⁶ is any suitabie alkyl (e.g Me). X¹² is any suitabie halide (e.g. Cl, Br, I). R¹⁷ is any suitabie alkyl that forms an ester group (e.g Me, Et, tBu). A compound of formula 8-1 may be prepared from 7-3 using any suitabie conditions known to those skilled in the art for the préparation of aryl boronic esters. In some embodiments, 4,4,5,5-tctramethyl-l,3,2-dîoxaborolane in the presence of a catalyst (e.g. Pd(dppf)C12) and an organic base (triethylamine) may be used. The reaction may be perfonned in a solvent such as xylene with added heat (150 °C). A compound of Formula 8-1 may react with an aryl halide of Formula 8-2 using any suitabie condition known to those skilled in the art, such as those for a Suzuki coupling reaction. In some embodiments, a catalyst such as Pd(dppi)Cb is used. In some 160 embodiments, the reaction may be performed in the presence of a base (e.g. Na₂CO₃) în a polar solvent (e.g. 1,4-dioxane) at elevated température (95 °C). Any suitable condition for the hydrolysîs of an ester, and removal of a nitrogen protecting group, may be used in the conversion of compounds of Formula 8-3 to compounds of Formula 7-3. In some embodiments, an aqueous solution of base (e.g. NaOH or KOH) in a polar solvent (e.g. a THF and MeOH mixture) may be used. The reaction may be performed with added heat (e.g. 55 °C). In alternative embodiments, the reaction may be performed in the presence of an amine (e.g. piperidine).

Scheme 8

Scheme 9 depicts an alternative process for the préparation of compounds of Fonnula 73. X¹³ is any suitable halogen (e.g. I, Br or Cl). X¹⁴ is any suitable halogen (e.g. I, Br or Ci). R¹⁸ is any suitable alkyl group that forms an ester (e.g. Me or Et). Other variables are as defined in Fonnula I. In some embodiments, a compound of Formula 9-3 may be prepared by reaction of compounds of Fonnula 9-1 with compounds of Formula 9-2. Any suitable conditions for coupling of an amine and aryl halide may be used. For example, a palladium catalyst System (e.g. tBuXPhos Pd G4) and a base (e.g. NaOtBu) may be used. Compounds of Formula 9-4 may be prepared from 9-3 using any suitable reagent for the protection of a nitrogen atom. A compound of formula 9-4 may react with an alkyne of Fonnula 9-5 under suitable conditions to give a compound of Formula 9-6. For example, in the presence of a catalyst system (e.g. Pd(P_tBu₃)₂, or Pd(OAc)₂ with a ligand such as DTBPF) . In some embodiments, the reaction is performed in the presence of a base (e.g. A-methyldicyclohexylamine, KHCO₃ or K₂CO₃). A compound of Fonnula 7-3 may be prepared from 9-6 using any suitable conditions for the 161 removal of a nitrogen protecting group such as PG¹, and the simultaneous hydrolysis of an ester group. For example, in some embodiments the reaction may be performed în the presence of a base (e.g. NaOH, KOH or NaOH and piperidine). The reaction may be performed in a polar solvent system (THF, MeOH, EtOH, water) with added heat (70 °C).

Scheme 9

Non-limiting exemplary embodiments include:

1. A compound of formula (I):

a tautomer thereof, a pharmaceutically acceptable sait of any of the foregoing, and/or a deuterated dérivative of any of the foregoing;

wherein:

(i) R° is chosen from (a) Ci-C₈ linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 R^A; and (b) 5- to 14-membered aromatic rings optionally substituted with 1-4 R^A;

162 wherein each R^A is independently chosen from halogens, cyano, hydroxy, thiol, sulfonic acid, sulfonamide, sulfinamide, amino, amide, carboxylic acid, 5- to 10membered aromatic rings, and Ci-Ce linear, branched, and cyclic groups, wherein the amide nitrogen atom in the amide of R^A is optionally substituted with a heterocyclyl group that is optionally further substituted with oxo, wherein the Ci-Cè linear, branched, and cyclic groups are chosen from alkyl, alkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, alkylsulfonamide, alkylsulfmamide, aminoalkyl, and alkylamide, wherein the 5- to 10-membered aromatic rings and Ci-Cf, linear, branched, and cyclic groups are optionally substituted with 1-4 substituents selected from halogens, Ci-C& linear, branched, and cyclic groups and methoxy, and wherein an R^A group is optionally linked to an R^B group on an R² group;

(ii) R¹ is chosen from (a) hydrogen, (b) Cj-C_s linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, cyanoalkyl, hydroxy, alkylsulfonyl, and

Ci-Cé linear, branched, and cyclic groups, wherein the C|-Cs linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the CpCé linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and

Ci-Cô linear, branched, and cyclic alkoxy groups, (c) Ci-C₈ linear, branched, and cyclic alkoxy or cyclic thioalkyl groups optionally substituted with 1 -4 substituents independently chosen from halogens, cyano, cyanoalkyl;

sulfone, sulfonamide,

163 hydroxy, and

Cj-C₆ linear, branched, and cyclic alkyl groups that are optionally substituted with l-4 halogens or alkoxy groups (d) Cj-Cô linear, branched, and cyclic alkylsulfonyl groups optionally substituted with Cj-Cô linear or branched alkyl groups;

(e) aminosulfbnyl groups, optionally substituted with l or 2 substituents independently chosen from

Cj-Cô linear, branched, and cyclic alkyl groups;

(f) Cj-Cô linear, branched, and cyclic alkylsulfonyl amino groups; and (g) phosphine oxide groups, optionally substituted with l or 2 substituents independently chosen from

Cj-Cô linear, branched, and cyclic alkyl groups;

(h) C|-Cô linear, branched, and cyclic trialkylsilyl groups;

(i) Cj-C₆ alkylamide;

(iii) R is chosen from 5- and 6-membered heterocyciic rings (optionally substituted with oxo and/or Cj-Cô linear and branched alkyl groups) and 5- to 6-membered aromatic rings comprising 0-4 heteroatoms chosen from O, N, and S, wherein the 5-membered aromatic ring îs optionally substituted with l -4 R^B groups and the 6-membercd aromatic ring is optionally substituted with l-5 R^B groups, wherein the R^B groups are independently chosen from:

amides, optionally substituted with l-3 groups selected from Cj-Cô linear, branched, and cyclic alkyl groups (optionally substituted with heteroaryl), 4- to 6membered heterocyclyl (optionally substituted with oxo, Cj-Cô linear, branched, and cyclic alkyl groups, hydroxyalkyl, amide, alkylsulfonyl, and acetamide); or wherein the amide nitrogen atom forms part of a 3- to 8-membered heterocyclyl ring (optionally substituted with alkylsulfonyl or Cj-Cô linear, branched, and cyclic alkyl group), imidazolidine-2,4-dione, heterocyclyls, optionally substituted with one more groups independently chosen from oxo, acyl, and Ci-C₆ linear, branched, and cyclic alkyl group (which is optionally further substituted with 1-3 groups independently chosen from oxo, hydroxy, and acyl), phosphorous acid optionally esterified with a C|-C₆ linear, branched, or cyclic alkyl group, di(Cj-Cô)alkylphosphine oxides, (Ci-Cô)alkylphosphinic acids optionally esterified with a Cj-Cô linear, branched, or cyclic alkyl group, halogens,

164 cyano, hydroxy, carboxylic acids optionally esterified with a uronic acid or a C|-C& linear, branched, or cyclic alkyl group, oxo, dihydroxylboryl,

5- and 6-membered aromatic rings comprising 0-4 heteroatoms independently chosen from O, N, and S, optionally substituted with l or 2 substituents independently chosen from Ci-Cô linear, branched, and cyclic alkyl groups that are optionally substituted with l-4 substituents independently chosen from hydroxy, carboxylic acids, pyrrolidîn-2-one, C|-Cô linear, branched, and cyclic alkyl groups, and

Cj-Cô linear, branched, and cyclic alkylsulfonyl groups, and

Ci-Cô linear, branched, and cyclic alkoxy groups, sulfonic acid, alkyl sulfonamide,

Ci-Cô linear, branched, and cyclic alkylsulfonyl groups, amînosulfonyl groups, optionally substituted with 1 or 2 substituents independently chosen from

C[-Cô linear, branched, and cyclic alkyl groups,

C|-Cô linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, carboxylic acid,

Cj-Cô linear, branched, and cyclic alkoxy groups, heterocyclyl optionally substituted with oxo, and amide,

Ci-Cô linear, branched, and cyclic alkoxy groups that are optionally substituted with 1 -4 substituents independently chosen from halogens, hydroxy, carboxylic acid,

165

Cj-Cô linear, branched, and cyclic alkyl groups, and Cj-Cô linear, branched, and cyclic alkoxy groups, and tetrazolyl groups that are optionally substituted with substituents chosen from halogens, hydroxy, carboxylic acid, Cj-Cô linear, branched, and cyclic alkyl groups, and Cj-Cô linear, branched, and cyclic alkoxy groups, wherein 2 adjacent hydrogens on the 5- or 6-membered aromatic ring can be replaced b y attachments to a second 5- or 6-membered aromatic ring comprising 0-4 heteroatoms independently chosen from O, N, and S to form a bicyclic R² group that is optionally substituted with 1-6 R^B groups;

(iv) X¹ and X² are independently chosen from hydrogen, halogens, cyano, hydroxy, Cj-Cô linear, branched, and cyclic groups wherein the Cj-Cô linear, branched, and cyclic groups are independently chosen from alkyl, alkoxy, thioalkyl, and aminoalkyl groups, and wherein the CjCô linear, branched, and cyclic groups are optionally substituted by 1 -4 independently chosen halogens;

(v) each of W¹ and W² is independently selected from C and N;

(vi) each j. - represents a single or double bond, provided that no more than one---is a double bond;

(vii) each R³ is independently chosen from hydrogen, halogens, cyano, Cj-Cô linear, branched, and cyclic alkyl groups, and C|-C₆ linear, branched, and cyclic alkoxy groups, wherein the Cj-Cô linear, branched, and cyclic alkyl groups and the Cj-Cô linear, branched, and cyclic alkoxy groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy groups, and carboxylic acid;

(viii) n is an integer chosen from 0, 1,2, and 3; and 12 3 (ix) Z‘, Z\ and Z are independently chosen from carbon, nitrogen, sulfur, and oxygen, wherein when Z , Z , and/or Z are carbon or nitrogen, the valences of carbon and nitrogen are completed with hydrogen atoms, halogen, C|-C₆ linear, branched, and cyclic alkyl groups, and Cj-C₆ linear, branched, and cyclic alkoxy groups, wherein the Cj-Cô linear, branched, and cyclic alkyl groups and the Cj-Cô linear, branched, and cyclic alkoxy groups are optionally substituted with 1 -4 substituents independently chosen from halogens, hydroxy groups, and carboxylic acid.

166

2. The compound according to embodiment l, a tautomer thereof, a pharmaceutically acceptable sait of the compound, a phannaceutically acceptable sait of the tautomer, a deuterated derivatîve of the compound, a deuterated derivatîve of the tautomer, and/or a deuterated derivatîve of the sait, wherein R° is chosen from aryl rings, heteroaryl rings, and Ci-Cg linear, branched, and cyclic alkyl groups, each of which is optionally substituted with 1-2 substituents independently chosen from halogen, carboxylic acid, Cj-Cé linear, branched, and cyclic alkyl groups, C|-C& linear, branched, and cyclic alkoxy groups, aryl rings, and heteroaryl rings.

3. The compound according to embodiment 1 or 2, a tautomer thereof, a pharmaceutically acceptable sait ofthe compound, a pharmaceutically acceptable sait of the tautomer, a deuterated derivatîve of the compound, a deuterated derivatîve of the tautomer, and/or a deuterated derivatîve of the sait, wherein R° is chosen from:

4. The compound according to any one of embodiments 1 to 3, a tautomer thereof, a pharmaceutically acceptable sait of the compound, a pharmaceutically acceptable sait of the tautomer, a deuterated derivatîve of the compound, a deuterated derivatîve of the tautomer, and/or a deuterated derivatîve of the sait, wherein R¹ is chosen from:

167

5. The compound according to any one of embodiments i to 4, a tautomer thereof a pharmaceutically acceptable sait of the compound, a pharmaceutically acceptable sait of the tautomer, a deuterated derivatîve of the compound, a deuterated derivatîve of the tautomer, and/or a deuterated derivatîve of the sait, wherein R² is chosen from:

6. The compound according to any one of embodiments 1 to 5, a tautomer thereof, a pharmaceutically acceptable sait of the compound, a pharmaceutically acceptable sait of the tautomer, a deuterated derivatîve of the compound, a deuterated derivatîve of the tautomer, and/or a deuterated derivatîve of the sait, wherein two of Z¹, Z², and Z³ are nitrogen and the other is chosen from carbon and nitrogen.

7. The compound according to any one of embodiments 1 to 6, a tautomer thereof, a pharmaceutically acceptable sait of the compound, a pharmaceutically acceptable sait of the tautomer, a deuterated derivatîve of the compound, a deuterated derivatîve of the tautomer, and/or a deuterated derivatîve of the sait, wherein each R³ is independently chosen from hydrogen, deuterium, halogen, C_rC₆ linear alkyl groups, and heterocyclyl groups.

16S

8. The compound according to any one of embodiments 1 to 7, a tautomer thereof, a phannaceutically acceptable sait of the compound, a phannaceutically acceptable sait of the tautomer, a deuterated dérivative ofthe compound, a deuterated dérivative ofthe tautomer, and/or a deuterated dérivative of the sait, wherein X¹ and X² are independently chosen from 5 hydrogen and halogen.

9. The compound according to embodiment 1 chosen from compounds of Fonnula I-A, I-B,

1-C, I-D, I-E, I-F, I-G, and I-II:

l-A l-B l-C

l-D l-E γ19

l-G

l-H a tautomer thereof, a pharmaceutically acceptable sait of the compound, a phannaceutically acceptable sait of the tautomer, a deuterated dérivative of the compound, a deuterated dérivative of the tautomer, and/or a deuterated dérivative of the sait, wherein:

R°, R¹, R², R³, and n are defined for compounds of Formula (I)

X¹ and X² are independently chosen from hydrogen and fluorine, or X¹ îs fluorine and X² is hydrogen, or X² is fluorine and X¹ is hydrogen, or X¹ and X² are each hydrogen, each of W¹ and W² is independently selected from C and N,

169

Y¹, Y², Y³, and Y⁴ are independently chosen from hydrogen, cyano, halogen groups, Cj-Cô linear, branched, and cyclic alkyi groups, Ci-Cô linear, branched, and cyclic alkoxy groups that are optionally substituted with 1-4 substituents independently chosen from hydroxy, Ci-Cô linear, branched, and cyclic alkyi groups, and C|-Cô linear, branched, and cyclic alkoxy groups;

Y⁵, Y⁶, Y⁷, and Y⁸ are independently chosen from hydrogen, halogen groups, hydroxy,

Ci-Cô linear, branched, and cyclic alkyi groups optionally substituted with 1-4 independently chosen halogen substituents, and

C|-Cô linear, branched, and cyclic alkoxy groups, Y⁹, Y’, Y¹¹, Y¹², Y¹³, Y¹⁴, Y¹⁵, and Y¹⁶ are independently chosen from carboxylic acid, hydrogen, halogen groups,

C|-C₆ linear, branched, and cyclic alkylsulfonyl groups,

Ci-Cô linear, branched, and cyclic alkyi groups optionally substituted with 1-4 independently chosen halogen substituents, and

Cj-Cè linear, branched, and cyclic alkoxy groups, Y¹⁷, Y¹⁸, Y¹⁹, Y²⁰, and Y²¹ are independently chosen from hydrogen, carboxylic acid, halogen groups, cyano, hydroxy,

C|-Cô linear, branched, and cyclic alkyi groups that are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and

170 carboxylic acid,

Cj-Ce linear, branched, and cyclic alkoxy groups that are optionally substituted with a carboxylic acid group, dihydroxyboryl, sulfonic acid, carboxylic acid optionally esterified with a uronic acîd, tetrazolyl groups, aminosulfonyl groups, optionally substituted with 1 or 2 substituents independently chosen from

C_rC₆ linear, branched, and cyclic alkyl groups, and

C|-Cè linear, branched, and cyclic alkylsulfonyl groups with theproviso that, in Formula I-E, at least one of Y¹⁷, Y^IR, Y¹⁹, Y^z0, and Y²’ is hydrogen.

10. The compound according to embodiment 9, a tautomer thereof, a pharmaceutically acceptable sait ofthe compound, a phannaceutically acceptable sait of the tautomer, a deuterated dérivative of the compound, a deuterated dérivative of the tautomer, and/or a deuterated dérivative of the sait, wherein one or more of Y¹⁷, Y¹⁸, Y¹⁹, Y²⁰, and Y²¹ is chosen from methyl, methoxy, cyano, fluorine, hydroxy, -CF₃, -B(OH)₂, -SO₂NHMe, -SO₂Me, -SO₂H, -CH₂CO₂H,

11. A compound chosen from:

171

172

173

174

175

I76

177

178

179

180

ISl

1S2

183

184

185

I86

187

188

189

190

I9l

192

193

194

195

196

I97

198

199

200

201

202

203

204

205

206

207

208

a tautomer thereof, a pharmaceutically acceptable sait of the compound, a pharmaceutically acceptable sait ofthe tautomer, a deuterated dérivative of the compound, a deuterated dérivative of the tautomer, and a deuterated dérivative of the sait.

12. A pharmaceutical composition comprising a compound according to anyone of embodiments I to 11, a tautomer thereof, a pharmaceutically acceptable sait of the compound, a phannaceutically acceptable sait of the tautomer, a deuterated dérivative ofthe compound, a deuterated dérivative of the tautomer, and/or a deuterated dérivative of the sait, and a pharmaceutically acceptable carrier.

13. A method of treating alpha-1 antitrypsin deficiency comprising administering to a patient in need thereof at least one compound chosen from the compounds, the tautomers, phannaceutically acceptable salts, and the deuterated dérivatives according to any one of embodiments 1 to 11, or comprising administering to a patient in need thereof a pharmaceutical composition according to embodiment 12.

209

14, The method according to embodiment 13, wherein the patient has a Z mutation in alpha-1 antitrypsin.

15. The method according to embodiment 14, wherein the patient has an SZ mutation in alpha-1 antitrypsin.

16. The method according to embodiment 14, wherein the patient is homozygous for Zmutations in alpha-1 antitrypsin.

17. A method of modulating alpha-1 antitrypsin activity comprising contacting said alpha-1 antitrypsin with at least one compound chosen from the compounds, the tautomers, pharmaceutically acceptable salts, and the deuterated dérivatives according to any one of embodiments 1 to 11, or contacting said alpha-1-antitrypsin with a pharmaceutical composition according to embodiment 12.

S. A compound of formula (Γ):

a tautomer thereof, a pharmaceutically acceptable sait of any of the foregoing, and/or a deuterated dérivative of any of the foregoing;

wherein:

(i) R⁰' is chosen from (a) C|-C₈ linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 R^A'; and (b) 5- to 14-membered aromatic rings optionally substituted with 1-4 R^A', wherein each R^A' is independently chosen from halogens, cyano, hydroxy, thiol, sulfonic acid, sulfonamide, sulfinamide, amino, amide, 5- to 10-membered aromatic rings, and C|-Cô linear, branched, and cyclic groups, wherein the Ci-Cô linear, branched, and cyclic groups are chosen from alkyl, alkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, alkyl sulfonamide, alkylsulfmamide, aminoalkyl, and alkylamide, and wherein the 5- to 10-membered aromatic rings and C_rCô linear, branched, and cyclic groups are optionally substituted with 1-4 substituents selected from halogens and methoxy, and

210 wherein an R^A' group is optionally linked to an R^B' group on an R²' group;

(ii) R¹' is chosen from (a) hydrogen, (b) Cj-Cg linear, branched, and cyclic alkyl groups, wherein the alkyl group îs optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and

C_rC₆ linear, branched, and cyclic groups, wherein the Ci-Cé linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the C|-Cs linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and

Cj-Cô linear, branched, and cyclic alkoxy groups, (c) C_rC_g linear, branched, and cyclic alkoxy or cyclic thioalkyl groups optionally substituted with 1-4 substituents independently chosen from halogens, cyano, sulfone, sulfonamide, hydroxy, and

Ci-C₆ linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 halogens;

(d) Cj-C₆ linear, branched, and cyclic alkylsulfonyl groups;

(e) aminosulfonyl groups, optionally substituted with 1 or 2 substituents independently chosen from

C_rC₆ linear, branched, and cyclic alkyl groups;

(f) Cj-C₆ linear, branched, and cyclic alkylsulfonyl amino groups;

(g) phosphine oxide groups, optionally substituted with 1 or 2 substituents independently chosen from

Ci-C₆ linear, branched, and cyclic alkyl groups; and (h) C|-C₆ linear, branched, and cyclic trialkylsilyl groups;

211 (iii) R²' is chosen from 5- and 6-membered aromatic rings comprising 0-4 heteroatoms chosen from O, N, and S, wherein the 5-membered ring is optionally substituted with l-4 R^B' groups and the 6-membered ring is optionally substituted with l-5 R^B' groups, wherein the R^B' groups are independently chosen from optionally substituted amides, imidazolidine-2,4-dione, optionally substituted heterocyclyls, phosphorous acid optionally esterified with a Cj-Cô linear, branched, or cyclic alkyl group, lû di(Cj-Cô)alkylphosphine oxides, (Ci-C₆)alkylphosphinic acids optionally esterified with a C_rC₆ linear, branched, or cyclic alkyl group, halogens, cyano, 15 hydroxy, carboxylic acids optionally esterified with a uronic acid or a C|-C₆ linear, branched, or cyclic alkyl group, oxo, dihydroxylboryl, ²⁰ 5- and 6-membered aromatic rings comprising 0-4 heteroatoms independently chosen from O, N, and S, optionally substituted with l or 2 substituents independently chosen from C_rCô linear, branched, and cyclic alkyl groups that are optionally substituted with l-4 substituents independently chosen from hydroxy, carboxylic acids, pyrrolidin-2-one,

Ci-C₆ linear, branched, and cyclic alkyl groups, and

C|-C₆ linear, branched, and cyclic alkylsulfonyl groups, andC₍-C₆ linear, branched, and cyclic alkoxy groups, 30 sulfonic acid,

Cj-Cô linear, branched, and cyclic alkylsulfonyl groups, aminosulfonyl groups, optionally substituted with l or 2 substituents independently chosen from

Ci-Cô linear, branched, and cyclic alkyl groups,

212

Ci-Cô linear, branched, and cyclic alkyl groups that are optionally substituted with l-4 substituents independently chosen from halogens, hydroxy, carboxylic acid, and

C]-C₆ linear, branched, and cyclic alkoxy groups, Ci-Cô linear, branched, and cyclic alkoxy groups that are optionally substituted with l -4 substituents independently chosen from halogens, hydroxy, carboxylic acid,

Cj-Cé linear, branched, and cyclic alkyl groups, and

C|-Cô linear, branched, and cyclic alkoxy groups, and tetrazolyl groups that are optionally substituted with substituents chosen from halogens, hydroxy, carboxylic acid,

C|-Cé linear, branched, and cyclic alkyl groups, and

Cj-Q, linear, branched, and cyclic alkoxy groups, wherein 2 adjacent hydrogens on the 5- or 6-membered aromatic ring can be replaced by attachments to a second 5- or 6-membered aromatic ring comprising 0-4 heteroatoms independently chosen from O, N, and S to form a bicyclic R^2r group that is optionally substituted with 1-6 R^B' groups;

(iv) X¹' and X²' are independently chosen from hydrogen, halogens, cyano, hydroxy, Ci-C₆ linear, branched, and cyclic groups wherein the Ci-C₆ linear, branched, and cyclic groups are independently chosen from alkyl, alkoxy, thioalkyl, and aminoalkyl groups, and wherein the CiCô linear, branched, and cyclic groups are optionally substituted by 1-4 independently chosen halogens;

(v) each---represents a single or double bond, provided that no more than one---is a double bond;

(vi) each R ' is independently chosen from hydrogen, halogens, cyano, Ci-Cô linear, branched, and cyclic alkyl groups, and Ci-Cô linear, branched, and cyclic alkoxy groups, wherein the linear, branched, and cyclic alkyl and alkoxy groups are optionally substituted with 1-4 independently chosen halogens;

(vii) n- is an integer chosen from 0, 1,2, and 3; and

213

3 (viii) Z , Z ,and Z are independently chosen from carbon, nitrogen, sulfur, and oxygen, wherein when Z¹', Z²', and/or Z³' are carbon or nitrogen, the valences of carbon and nitrogen are completed with hydrogen atoms.

19. The compound according to embodiment 1 S, a tautomer thereof, a pharmaceutically acceptable sait ofthe compound, a pharmaceutically acceptable sait of the tautomer, a deuterated dérivative of the compound, a deuterated dérivative of the tautomer, and/or a deuterated dérivative of the sait, wherein R^fl' is chosen from heteroaryl rings.

20. The compound of embodiment 1 S, a tautomer thereof, a phannaceutically acceptable sait of the compound, a phannaceutically acceptable sait of the tautomer, a deuterated dérivative of the compound, a deuterated dérivative of the tautomer, and/or a deuterated dérivative of the sait, wherein Rⁿ' is phenyl.

21. The compound according to any one of embodiments 17 to 20, a tautomer thereof, a phannaceutically acceptable sait of the compound, a pharmaceutically acceptable sait of the tautomer, a deuterated dérivative of the compound, a deuterated dérivative of the tautomer, and/or a deuterated dérivative of the sait, wherein R^u' is unsubstituted.

22. The compound according to any one of embodiments 17 to 20, a tautomer thereof, a phannaceutically acceptable sait of the compound, a phannaceutically acceptable sait of the tautomer, a deuterated dérivative of the compound, a deuterated dérivative of the tautomer, and/or a deuterated dérivative ofthe sait, wherein R“'is substituted with 1-2 substituents.

23. The compound according to embodiment 22, a tautomer thereof, a phannaceutically acceptable sait of the compound, a pharmaceutically acceptable sait of the tautomer, a deuterated dérivative of the compound, a deuterated dérivative of the tautomer, and/or a deuterated dérivative ofthe sait, wherein the 1-2 substituents are independently chosen from halogens, CiC₄ alkyl groups, and C|-C₄ alkoxy groups.

24. The compound according to embodiment 23, a tautomer thereof, a pharmaceutically acceptable sait of the compound, a phannaceutically acceptable sait of the tautomer, a deuterated dérivative of the compound, a deuterated dérivative of the tautomer, and/or a deuterated dérivative of the sait, wherein the I -2 substituents are independently chosen from fluorine, methyl, and methoxy.

214

25. The compound according to embodiment 18, a tautomer thereof, a pharmaceutically acceptable sait of the compound, a pharmaceutically acceptable sait of the tautomer, a deuterated derivatîve of the compound, a deuterated derivatîve of the tautomer, and/or a deuterated derivatîve ofthe sait, wherein R¹' is chosen from C1-C4 linear and branched alkyl groups and C₄C(, cyclic alkyl groups.

26. The compound according to embodiment 25, a tautomer thereof, a pharmaceutically acceptable sait of the compound, a pharmaceutically acceptable sait of the tautomer, a deuterated derivatîve of the compound, a deuterated derivatîve of the tautomer, and/or a deuterated derivatîve of the sait, wherein R¹ ' is chosen from C₃ branched alkyl groups and C₆ cyclic alkyl groups.

27. The compound according to embodiment 26, a tautomer thereof, a pharmaceutically acceptable sait ofthe compound, a pharmaceutically acceptable sait of the tautomer, a deuterated derivatîve of the compound, a deuterated derivatîve of the tautomer, and/or a deuterated derivatîve ofthe sait, wherein R¹' is chosen from C₄-C₆ cyclic alkyl groups wherein 1 carbon atom is replaced by a heteroatom.

28. The compound according to embodiment 27, a tautomer thereof, a pharmaceutically acceptable sait of the compound, a pharmaceutically acceptable sait of the tautomer, a deuterated derivatîve of the compound, a deuterated derivatîve of the tautomer, and/or a deuterated derivatîve of the sait, wherein R¹' is chosen from C₆ cyclic alkyl groups wherein 1 carbon atom is replaced by a heteroatom.

29. The compound according to any one of embodiments 25-28, a tautomer thereof, a pharmaceutically acceptable sait of the compound, a pharmaceutically acceptable sait ofthe tautomer, a deuterated derivatîve of the compound, a deuterated derivatîve of the tautomer, and/or a deuterated derivatîve of the sait, wherein the alkyl group is substituted with a methyl, ethyl, methoxy, and/or hydroxy substituent.

30. The compound according to embodiment 18, a tautomer thereof, a pharmaceutically acceptable sait of the compound, a pharmaceutically acceptable sait of the tautomer, a deuterated derivatîve of the compound, a deuterated derivatîve of the tautomer, and/or a deuterated

215

Ο —S-R^c' i c, derivatîve of the sait, wherein R is chosen from O groups, wherein R is chosen from (a) C[-Cô linear, branched, and cyclic alkyl groups, (b) Ci-C& linear, branched, and cyclic alkyl groups substituted with 1 or 2 substituents independently chosen from Ci-C& linear alkyl groups, (c) C|-Cô linear alkyl groups, and (d) CrQ linear alkyl groups substituted with 1 or 2 substituents independently chosen from Cj-Cô linear alkyl groups, or wherein R¹' îs chosen from

O fs-N(R^D')₂

O groups, wherein each R^D' is independently chosen from (e) Ci-C₈ linear, branched, and cyclic alkyl groups and (f) Cj-Cg linear, branched, and cyclic alkyl groups substituted with 1 or 2 substituents independently chosen from C|-Cô linear alkyl groups, or wherein R¹' is chosen O

ViCH^-P-R⁰ from R groups, wherein each of R ” and R is independently chosen from (g)

Cj-Cg linear, branched, and cyclic alkyl groups and (h) Cj-Cg iinear, branched, and cyclic alkyl groups substituted with 1 or 2 substituents independently chosen from Cj-Cô linear alkyl groups.

31. The compound according to any one of embodiments 25-30, a tautomer thereof, a pharmaceutically acceptable sait of the compound, a pharmaceutically acceptable sait of the tautomer, a deuterated derivatîve of the compound, a deuterated derivatîve of the tautomer, and/or a deuterated derivatîve of the sait, wherein R¹ ' is chosen from:

hydrogen, methyl, trimethylsilyl, trifluoromethyl,

216

32. The compound according to embodiment 18, a tautomer thereof, a pharmaceutically acceptable sait of the compound, a pharmaceutically acceptable sait of the tautomer, a deuterated dérivative of the compound, a deuterated dérivative of the tautomer, and/or a deuterated dérivative of the sait, wherein at least one of Z¹ ', Z²', and Z³' is nitrogen.

33. The compound according to embodiment 32, a tautomer thereof, a pharmaceutically acceptable sait of the compound, a pharmaceutically acceptable sait of the tautomer, a deuterated dérivative ofthe compound, a deuterated dérivative of the tautomer, and/or a deuterated dérivative of the sait, wherein two of Z¹', Z²', and Z³' are nitrogen and the other is chosen from carbon and nitrogen.

34. The compound according to any one of embodiments 18 to 33, a tautomer thereof, a pharmaceutically acceptable sait of the compound, a phannaceutical 1 y acceptable sait ofthe tautomer, a deuterated dérivative of the compound, a deuterated dérivative of the tautomer, and/or a deuterated dérivative of the sait, wherein each R³’ is independently chosen from hydrogen and C|-Cô linear alkyl groups.

35. The compound according to any one of embodiments 18 to 35, a tautomer thereof, a phannaceutical 1 y acceptable sait of the compound, a pharmaceutically acceptable sait of the tautomer, a deuterated dérivative of the compound, a deuterated dérivative ofthe tautomer, and/or a deuterated dérivative of the sait, wherein X¹ ' and X²' are independently chosen from hydrogen and halogen.

36. The compound according to embodiment 35, a tautomer thereof, a pharmaceuticallv acceptable sait of the compound, a phannaceutical ly acceptable sait of the tautomer, a deuterated dérivative of the compound, a deuterated dérivative of the tautomer, and/or a deuterated dérivative of the sait, wherein X¹' and X²' are each hydrogen.

37. The compound according to embodiment 18 chosen from compounds of Formula LA', IB , LC', LD , LE , LF', LG', and LH

217

γ19'

a tautomer thereof, a phannaceutically acceptable sait of the compound, a phannaceutically acceptable sait of the tautomer, a deuterated dérivative of the compound, a deuterated dérivative of the tautomer, and/or a deuterated dérivative of the sait, wherein:

R⁰', R¹', R²', R³', and n- are defined for compounds of Formula (I')

X¹' and X²' are independently chosen from hydrogen and fluorine, or X¹' îs fluorine and X²' is hydrogen, or X²' is fluorine and X¹' is hydrogen, or X¹' and X²' are each hydrogen,

Y¹', Y²', Y³', and Y⁴' are independently chosen from hydrogen, cyano, halogen groups,

Ci-Cô linear, branched, and cyclic alkyi groups,

C_rC₆ linear, branched, and cyclic alkoxy groups that are optionally substituted with 1-4 substituents independently chosen from hydroxy, C]-Cf, linear, branched, and cyclic alkyi groups, and

Cj-C₆linear, branched, and cyclic alkoxy groups;

218

6 7 8

Y , Y', Y, and Y“ are independently chosen from hydrogen, halogen groups hydroxy,

Ci-Cô linear, branched, and cyclic alkyl groups optionally substituted with l-4 independently chosen halogen substituents, and

Cj-Cé linear, branched, and cyclic alkoxy groups, γ9 , γ¹⁰', γ¹¹ ' Yn; γ¹³γ^,4'? γ¹⁵', and Y¹⁶' are independently chosen from carboxylic acid, 10 hydrogen, halogen groups,

Ci-Cô linear, branched, and cyclic alkylsuifonyl groups, Ci-Cô linear, branched, and cyclic alkyl groups optionally substituted with 1-4 independently chosen halogen substituents, and

C_rC₆ linear, branched, and cyclic alkoxy groups,

Y¹⁷', Y¹⁸', Y¹⁹', Y²⁰', and Y²¹'are independently chosen from hydrogen, carboxylic acid, halogen groups, cyano, hydroxy,

Ci-C₆ linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and carboxylic acid,

Ci-Cô linear, branched, and cyclic alkoxy groups that are optionally substituted with a carboxylic acid group, dihydroxyboryl, sulfonic acid, carboxylic acid optionally esterified with a uronic acid, tetrazolyl groups, aminosulfonyl groups, optionally substituted with I or 2 substituents independently chosen from ³⁵ C_rC₆ linear, branched, and cyclic alkyl groups, and

219

C|-Cô linear, branched, and cyclic alkylsulfonyl groups with the proviso that, in Formula Ï-E', at least one of Y¹⁷', Y^,s\ γ¹⁹', γ²⁰ j and Y²¹ is hydrogen.

38. The compound according to embodiment 37, a tautomer thereof, a phaimaceutîcally acceptable sait ofthe compound, a phannaceutically acceptable sait of the tautomer, a deuterated derîvative of the compound, a deuterated derîvative of the tautomer, and/or a deuterated derîvative ofthe sait, wherein one or more of Y¹⁷', Y¹⁸\ Y¹⁹', Y²⁰', and Y^2I'is chosen from methyl, methoxy, cyano, fluorine, hydroxy, -CF₃, -B(OH)₂, -SO₂NHMe, -SO₂Me, -SO₂H,

-CH₂CO₂H,

39. A phannaceuticai composition comprising a compound according to embodiment 18, a tautomer thereof, a pharmaceutically acceptable sait of the compound, a phannaceutically acceptable sait of the tautomer, a deuterated derîvative of the compound, a deuterated derîvative of the tautomer, and/or a deuterated derîvative of the sait, and a phannaceutically acceptable carrier.

40. A method of treating alpha-1 antitrypsin deficiency comprising administering to a patient in need thereof at least one compound chosen from the compounds, the tautomers, pharmaceutically acceptable salts, and the deuterated dérivatives according to any one of embodiments 18 to 38 or a pharmaceutical composition according to embodiment 39.

41. The method according to embodiment 40, wherein the patient has a Z mutation in alpha-1 antitrypsin.

42. The method according to embodiment 41, wherein the patient has an SZ mutation in alpha-1 antitrypsin.

43. The method according to embodiment 41, wherein the patient is homozygous for Zmutations in alpha-1 antitrypsin.

220

44. A method of modulating alpha-1 antitrypsin activity comprising contacting said alpha-1 antitrypsin with at least one compound chosen from the compounds, the tautomers, pharmaceutically acceptable salts, and the deuterated derivatives according to any one of embodiments IS to 38 or a pharmaceutical composition according to embodiment 39.

45. Substantially crystalline Compound 33 Fonn A (Compound 33).

46. The Compound 33 Form A according to Embodiment 45, wherein Compound 33 is substantially pure crystalline Compound 33 Fonn A.

47. The Compound 33 Fonn A according to Embodiment 45 or Embodiment 46, w^rherein Compound 33 Fonn A is characterized by an X-ray powder diffractogram having signais at one or more of 19.2 ± 0.2 degrees two-theta, 19.5 ± 0.2 degrees two-theta, 15.5 ± 0.2 degrees twotheta, and 17.5 ± 0.2 degrees two-theta.

48. The Compound 33 Form A according to Embodiment 45 or Embodiment 46, wherein Compound 33 Fonn A is characterized by an X-ray powder diffractogram having signais at 19.2 ± 0.2 degrees two-theta, 19.5 ± 0.2 degrees two-theta, 15.5 ± 0.2 degrees two-theta, and 17.5 ± 0.2 degrees two-theta.

49. The Compound 33 Form A according to Embodiment 45 or Embodiment 46, wherein Compound 33 Fonn A is characterized by an X-ray powder diffractogram having signais at (a) 19.2 ± 0.2 degrees two-theta, 19.5 ± 0.2 degrees two-theta, 15.5 ± 0.2 degrees two-theta, and 17.5 ± 0.2 degrees two-theta; and (b) at least one, at least two, at least three, at least four, or at least five signais selected from 11.0 ± 0.2 degrees two-theta, 14.2 ± 0.2 degrees two-theta, 16.0 ± 0.2 degrees two-theta, 16.2 ± 0.2 degrees two-theta, 20.9 ± 0.2 degrees two-theta, 21.3 ± 0.2 degrees two-theta, 21.8 ± 0.2 degrees two-theta, and 25.5 ± 0.2 degrees two-theta.

221

50. The Compound 33 Form A according to Embodiment 45 or Embodiment 46, wherein Compound 33 Form A is characterized by an X-ray powder diffractogram having signais at 11.0 ± 0.2 degrees two-theta, 14.2 ± 0.2 degrees two-theta, 15.5 ± 0.2 degrees two-theta, 16.0 ± 0.2 degrees two-theta, 16.2 ± 0.2 degrees two-theta, 17.5 ± 0.2 degrees two-theta, 19.2 ± 0.2 degrees two-theta, 19.5 ± 0.2 degrees two-theta, 20.9 ± 0.2 degrees two-theta, 21.3 ± 0.2 degrees twotheta, 21.8 ± 0.2 degrees two-theta, and 25.5 ± 0.2 degrees two-theta.

51. The Compound 33 Form A according to Embodiment 45 or Embodiment 46, wherein Compound 33 Form A is characterized by an X-ray powder diffractogram substantially similar to FIG. IA.

52. The Compound 33 Form A according to any one of Embodiments 45-5 i, wherein Compound 33 Form A is characterized by a ^,3C solid State nuclear magnetic résonance (¹³C ssNMR) spectrum with one, two, three, four, five, six, seven, or more 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.

53. The Compound 33 Form A according to any one of Embodiments 45-51, wherein Compound 33 Form A is characterized by a ^l3C 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.

54. The Compound 33 Form A according to any one of Embodiments 45-51, wherein Compound 33 Form A is characterized by a ^l3C ssNMR spectrum substantially similar to FIG. IB.

55. The Compound 33 Form A according to any one of Embodiments 45-54, wherein Compound 33 Form A is characterized by a ¹⁹F solid state nuclear magnetic résonance (^I9F ssNMR) spectrum having a peak at -109.3 ± 0.2 ppm.

56. The Compound 33 Form A according to any one of Embodiments 45-54, wherein

Compound 33 Form A is characterized by a ^l9F ssNMR spectrum substantially similar to FIG

IC.

222

57. A pharmaceutical composition comprising the Compound 33 Form A according to any one of Embodiments 45-56 and a phannaceutically acceptable carrier.

58. A method of treating alpha-1 antitrypsin deficiency comprising administering to a patient in need thereof the Compound 33 Fonn A according to any one of Embodiments 45-56, or a phannaceutical composition according to Embodiment 57.

59. The method according to Embodiment 58, wherein the patient has a Z mutation in alphal antitrypsin.

60. The method according to Embodiment 58, wherein the patient has an SZ mutation in alpha-1 antitrypsin.

61. The method according to Embodiment 58, wherein the patient is homozygous for Zmutations in alpha-1 antitrypsin.

62, Use of the Compound 33 Fonn A according to any one of Embodiments 45-56 in the manufacture of a médicament for treating alpha-1 antitrypsin deficiency.

63. Substantially crystalline Compound 33 Fonn B.

64. The Compound 33 Form B according to Embodiment 63, wherein Compound 33 is substantially pure crystalline Compound 33 Form B.

65. The Compound 33 Form B according to Embodiment 63 or Embodiment 64, wherein Compound 33 Form B is characterized by an X-ray powder diffractogram having signais at one or more of 20.2 ± 0.2 degrees two-theta, 9.2 ± 0.2 degrees two-theta, 4.5 ± 0.2 degrees two-theta, and 15.1 ± 0.2 degrees two-theta.

66. The Compound 33 Fonn B according to Embodiment 63 or Embodiment 64, wherein

Compound 33 Form B is characterized by an X-ray powder diffractogram having signais at 20.2 ± 0.2 degrees two-theta, 9.2 ± 0.2 degrees two-theta, 4.5 ± 0.2 degrees two-theta, and 15.1 ± 0.2 degrees two-theta.

223

67. The Compound 33 Form B according to Embodiment 63 or Embodiment 64, wherein Compound 33 Fonn B is characterized by an X-ray powder diffractogram having signais (a) at 20.2 ± 0.2 degrees two-theta, 9.2 ± 0.2 degrees two-theta, 4.5 ± 0.2 degrees two-theta. and I5.l ± 0.2, and (b) at least one, at least two, at least three, at least four, at least five, at least six, at least eight, or at least ten signais selected from 9.9 ± 0.2 degrees two-theta, 11.0 ± 0.2 degrees twotheta, 12.7 ± 0.2 degrees two-theta, 14.3 ± 0.2 degrees two-theta, 16.2 ± 0.2 degrees two-theta, 16.8 ± 0.2 degrees two-theta, 17.1 ± 0.2 degrees two-theta, 18.1 ± 0.2 degrees two-theta, 18.4 ± 0.2 degrees two-theta, 19.8 ± 0.2 degrees two-theta, 20.6 ± 0.2 degrees two-theta, 21.4 ± 0.2 degrees two-theta, 22.3 ± 0.2 degrees two-theta, 23.6 ± 0.2 degrees two-theta, 24.7 ±0.2 degrees two-theta, 26.6 ± 0.2 degrees two-theta, 27.4 ± 0.2 degrees two-theta, and 28.9 ± 0.2 degrees two-theta.

68. The Compound 33 Fonn B according to Embodiment 63 or Embodiment 64, wherein Compound 33 Form B is characterized by an X-ray powder diffractogram having signais at 4.5 ± 0.2 degrees two-theta, 9.2 ± 0.2 degrees two-theta, 15.1 ± 0.2 degrees two-theta, 17.1 ± 0.2 degrees two-theta, 18.1 ± 0.2 degrees two-theta, 20.2 ± 0.2 degrees two-theta, 22.3 ± 0.2 degrees two-theta, 26.6 ± 0.2 degrees two-theta, and 27.4 ± 0.2 degrees two-theta.

69. The Compound 33 Form B according to Embodiment 63 or Embodiment 64, wherein Compound 33 Fonn B is characterized by an X-ray powder diffractogram substantially similar to FIG. 2A.

70. The Compound 33 Fonn B according to any one of Embodiments 63-69, wherein Compound 33 Form B is characterized by a ^l3C solid State nuclear magnetic résonance (¹³C ssNMR) spectrum with one, two, three, four, five, six, seven, or more 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.

71. The Compound 33 Fonn B according to any one of Embodiments 63-69, wherein Compound 33 Fonn B is characterized by a ^l3C 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.

224

72. The Compound 33 Form B according to any one of Embodiments 63-69, wherein Compound 33 Fonn B is characterized by a ⁱ³C ssNMR spectrum substantially similar to FIG.

2B.

73. The Compound 33 Fonn B according to any one of Embodiments 63-72, wherein Compound 33 Form B is characterized by a ^l9F solid State nuclear magnetic résonance (¹⁹F ssNMR) spectrum having a peak at one or more of -110.2 ± 0.2 ppm, 111.6 ± 0.2 ppm, and 115.6 ± 0.2 ppm.

74. The Compound 33 Fonn B according to anyone of Embodiments 63-72, wherein Compound 33 Form B is characterized by a ^l9F ssNMR spectrum substantially similar to FIG 2C

75. A phannaceuticai composition comprising the Compound 33 Fonn B according to any one of Embodiments 63-74 and a pharmaceutically acceptable carrier.

76. A method of treating alpha-1 antitrypsin deficiency comprising administering to a patient in need thereof the Compound 33 Fonn B according to any one of Embodiments 63-74, or a pharmaceutical composition according to Embodiment 75.

77. The method according to Embodiment 76, wherein the patient has a Z mutation in alpha1 antitrypsin.

78. The method according to Embodiment 76, wherein the patient has an SZ mutation in alpha-1 antitrypsin.

79. The method according to Embodiment 76, wherein the patient is homozygous for Zmutations in alpha-1 antitrypsin.

80. Use of the Compound 33 Form B according to any one of Embodiments 63-74 in the manufacture of a médicament for treating alpha-1 antitrypsin deficiency.

81. Substantially crystalline Compound 33 Dichloromethane (DCM) Solvaté Form A.

225

82. The Compound 33 DCM Solvaté Form A according to Embodiment 81, wherein Compound 33 is substantially pure crystalline Compound 33 DCM Solvaté Form A.

83, The Compound 33 DCM Solvaté Fonn A according to Embodiment 81 or Embodiment 82, wherein Compound 33 DCM Solvaté Form A is characterized by an X-ray powder diffractogram having signais at one or more of 20.9 ± 0.2 degrees two-theta, 18.3 ± 0.2 degrees two-theta, and 14.4 ±0.2 degrees two-theta.

84. The Compound 33 DCM Solvaté Form A according to Embodiment 81 or Embodiment 82, wherein Compound 33 DCM Solvaté Form A îs characterized by an X-ray powder diffractogram having signais at 20.9 ± 0.2 degrees two-theta, 18.3 ± 0.2 degrees two-theta, and 14.4 ± 0.2 degrees two-theta.

85. The Compound 33 DCM Solvaté Fonn A according to Embodiment 81 or Embodiment 82, wherein Compound 33 DCM Solvaté Fonu A is characterized by an X-ray powder diffractogram having signais (a) at 20.9 ± 0,2 degrees two-theta, 18,3 ± 0.2 degrees two-theta, and 14.4 ± 0.2 degrees two-theta; and (b) at least one, at least two, at least three, at least four, at least five, at least six, at least eight, or at least ten signais selected from 7.1 ± 0.2 degrees twotheta, 8.8 ± 0.2 degrees two-theta, 9.0 ± 0.2 degrees two-theta, 10.1 ± 0.2 degrees two-theta, 13.3 ± 0.2 degrees two-theta, 13.9 ± 0.2 degrees two-theta, 17.2 ± 0.2 degrees two-theta, 20.3 ± 0.2 degrees two-theta, 21.7 ± 0.2 degrees two-theta, 22.6 ± 0.2 degrees two-theta, 22.8 ± 0,2 degrees two-theta, 23.4 ± 0.2 degrees two-theta, 24.0 ± 0.2 degrees two-theta, 26.6 ± 0.2 degrees twotheta, 27.1 ± 0.2 degrees two-theta, 27.7 ± 0,2 degrees two-theta, 28.3 ± 0.2 degrees two-theta.

86. The Compound 33 DCM Soivate Form A according to Embodiment 81 or Embodiment 82, wherein Compound 33 DCM Soivate Form A is characterized by an X-ray powder diffractogram substantially similar to FIG. 3A.

87. A pharmaceutical composition comprising the Compound 33 DCM Soivate Fonn A according to any one of Embodiments 81 -86 and a pharmaceutically acceptable carrier.

88. A method of treating alpha-1 antitrypsin deficiency comprising administering to a patient in need thereof the Compound 33 DCM Soivate Form A according to any one of Embodiments 81-86, or a pharmaceutical composition according to Embodiment 87.

226

89. The method according to Embodiment 88, wherein the patient has a Z mutation in alphal antitrypsin.

90. The method according to Embodiment 88, wherein the patient has an S Z mutation in alpha-1 antitrypsin.

9] . The method according to Embodiment 88, wherein the patient is homozygous tbr Zmutations in alpha-1 antitrypsin.

92. Use of the Compound 33 DCM Solvaté Fonn A according to any one of Embodiments 81-86 în the manufacture of a médicament for treating alpha-1 antitrypsin deficiency.

93. Substantially crystalline Compound 33 Hydrate Fonn A.

94. The Compound 33 Hydrate Form A according to Embodiment 93, wherein Compound 33 is substantially pure crystalline Compound 33 Hydrate Form A.

95. The Compound 33 Hydrate Form A according to Embodiment 93 or Embodiment 94, wherein Compound 33 Hydrate Form A is characterized by an X-ray powder diffractogram having signais at one or more of 19.5 ± 0.2 degrees two-theta, 10.4 ± 0.2 degrees two-theta, and 16.6 ± 0.2 degrees two-theta.

96. The Compound 33 Hydrate Form A according to Embodiment 93 or Embodiment 94, wherein Compound 33 Hydrate Form A is characterized by an X-ray powder diffractogram having signais at 19.5 ± 0.2 degrees two-theta, 10.4 ± 0.2 degrees two-theta, and 16.6 ± 0.2 degrees two-theta.

97, The Compound 33 Hydrate Form A according to Embodiment 93 or Embodiment 94, wherein Compound 33 Hydrate Form A is characterized by an X-ray powder diffractogram having (a) signais at 19.5 ± 0.2 degrees two-theta, 10.4 ± 0.2 degrees two-theta, and 16.6 ± 0.2 degrees two-theta; and (b) at at least three, at least four, at least five, at least six, at least seven, at least eight, at least nîne, or ten signais selected from 13.6 ± 0.2 degrees two-theta, 18.4 ± 0.2 degrees two-theta, 17.5 ± 0.2 degrees two-theta, 18.9 ± 0.2 degrees two-theta, 20.8 ± 0.2 degrees two-theta, 21.1 ± 0.2 degrees two-theta, 21.4 ± 0.2 degrees two-theta, 21.6 ± 0.2 degrees twotheta, 21.8 ± 0.2 degrees two-theta, and 24.8 ± 0.2 degrees two-theta.

227

98. The Compound 33 Hydrate Fonn A according to Embodiment 63 or Embodiment 64, wherein Compound 33 Hydrate Form A is characterized by an X-ray powder diffractogram substantially similar to FIG. 4A.

99. The Compound Hydrate Form A according to Embodiment 93 or Embodiment 94, wherein Compound 33 Hydrate Form A is characterized by a triclinic crystal system, aP-l space group, and the following unit cell dimensions measured at 100 K on a Bruker diffractiometer equipped with Cu K_a radiation (λ=Ι.54!78 Â) and a CMOS detector:

a(Â)	9.98 ± .01
b (Â)	10.42 ± .01
c(Â)	11.30± .01
«o	74.06 ± .02
β(°)	78.91 ± .02
γ(°)	84.14 ± .02
V(Â3)	1107.3± 1.8
Z/Z'	2/1

100. The Compound 33 Hydrate Fonn A according to any one of Embodiments 93-99, wherein Compound 33 Hydrate Form A is characterized by a ^,3C solid state nuclear magnetic résonance ( C ssNMR) spectrum with one, two, three, four, five, six, seven, or more peaks selected from 172.3 ± 0.2 ppm, 141.6 ± 0.2 ppm, 134.8 ± 0.2 ppm, 132.4 ± 0.2 ppm, 129.6 ± 0.2 15 ppm, 123.1 ± 0.2 ppm, 32.8 ± 0.2 ppm, and 28.4 ± 0.2 ppm.

101. The Compound 33 Hydrate Form A according to any one of Embodiments 93-99, wherein Compound 33 Hydrate Form A is characterized b y a ^l3C ssNMR spectrum with peaks at 172.3 ± 0.2 ppm, 141.6 ± 0.2 ppm, 134.8 ± 0.2 ppm, 132.4 ± 0.2 ppm, 129.6 ± 0.2 ppm, 123.1 ± 20 0.2 ppm, 32.8 ± 0.2 ppm, and 28.4 ± 0.2 ppm.

102. The Compound 33 Hydrate Form A according to any one of Embodiments 93-99, wherein Compound 33 Hydrate Form A is characterized by a ¹³C ssNMR spectrum substantially similar to FIG. 4B.

228

103. The Compound 33 Hydrate Fonn A according to any one of Embodiments 93-i02, wherein Compound 33 Hydrate Form A is characterized by a ^l9F solid State nuclear magnetic résonance (^l9F ssNMR) spectrum having a peak at -103.1 ± 0.2 ppm.

104. The Compound 33 Hydrate Fonn A according to any one of Embodiments 93-102, wherein Compound 33 Hydrate Fonn A is characterized by a ^l9F ssNMR spectrum substantially similar to FIG 4C.

105. A pharmaceutical composition comprising the Compound 33 Hydrate Fonn A according to any one of Embodiments 93-104 and a phannaceutîcally acceptable carrier.

106. A method of treating alpha-1 antitrypsin deficiency comprising administering to a patient in need thereof the Compound 33 Hydrate Form A according to any one of Embodiments 93104, or a phannaceutical composition according to Embodiment 105.

107. The method according to Embodiment 106, wherein the patient has a Z mutation in alpha-1 antitrypsin.

108. The method according to Embodiment 106, wherein the patient has an SZ mutation în alpha-1 antitrypsin.

109. The method according to Embodiment 106, wherein the patient is homozygous for Zmutations in alpha-1 antitrypsin.

110. Use of the Compound 33 Hydrate Form A according to any one of Embodiments 94-104 in the manufacture of a médicament for treating alpha-1 antitrypsin deficiency.

111. Substantially crystalline Compound 33 MeOH/H₂O Solvate/Hydrate Form A.

112. The Compound 33 MeOH/H₂O Solvate/Hydrate Form A according to Embodiment 111, wherein Compound 33 îs substantially pure crystalline Compound 33 MeOH/H₂O Solvate/Hydrate Form A.

113. The Compound 33 MeOH/H₂O Solvate/Hydrate Fonn A according to Embodiment 111 or Embodiment 112, wherein Compound 33 MeOH/H₂O Solvate/Hydrate Form A is

229 characterized by an X-ray powder diffractogram having signais at one or more of 16.6 ± 0.2 degrees two-theta and 17.4 ± 0.2 degrees two-theta.

114. The Compound 33 MeOH/H₂O Solvate/Hydrate Form A according to Embodiment 111 or Embodiment 112, wherein Compound 33 MeOH/H₂O Solvate/Hydrate Form A is characterized by an X-ray powder diffractogram having signais at 16.6 ± 0.2 degrees two-theta and 17.4 ± 0.2 degrees two-theta.

115. The Compound 33 MeOH/H₂O Solvate/Hydrate Form A according to Embodiment 111 or Embodiment 112, wherein Compound 33 MeOH/H₂O Solvate/Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at (a) 16.6 ± 0.2 degrees twotheta and 17.4 ± 0.2 degrees two-theta and (b) one or more of 10.4 ± 0.2 degrees two-theta, 18.2 ± 0.2 degrees two-theta, and 19.4 ± 0.2 degrees two-theta.

116. The Compound 33 MeOH/H₂O Solvate/Hydrate Form A according to Embodiment 111 or Embodiment 112, wherein Compound 33 MeOH/H₂O Solvate/Hydrate Form A is characterized by an X-ray powder diffractogram having signais at 10.4 ± 0.2 degrees two-theta, 16.6 ± 0.2 degrees two-theta, 17.4 ± 0.2 degrees two-theta, 18.2 ± 0.2 degrees two-theta, and 19.4 ± 0.2 degrees two-theta.

117. The Compound 33 MeOH/H₂O Solvate/Hydrate Form A according to Embodiment 111 or Embodiment 112, wherein Compound 33 MeOH/H₂O Solvate/Hydrate Form A is characterized by an X-ray powder diffractogram substantially similar to FIG, SA.

118. The Compound MeOH/H₂O Solvate/Hydrate Form A according to Embodiment 111 or Embodiment 112, wherein Compound 33 MeOH/H₂O Solvate/Hydrate Form A characterized by a triclinic crystal system, a P-l space group, and the following unit cell dimensions measured at i 00 K on a Bruker diffractiometer equipped with Cu K„ radiation (λ=1.54178 Â) and a CMOS detector:

a (A)	10.02 ±.01
b (A)	10.43 ± .01
c(Â)	11.25± .01
	74.50 ± .01
β(°)	79.62 ± .01

230

γ(°)	84.98 ±.01
V(Â3)	1113.5 ± 1.8
Z/Z'	2/1

119. A pharmaceutical composition comprising the Compound 33 MeOH/H₂O Solvate/Hydrate Fonn A according to any one of Embodiments 111 - l 18 and a phannaceutically acceptable carrier.

120. A method of treating alpha-1 antitrypsin deficiency comprising administering to a patient in need thereof the Compound 33 McOH/HaO Solvate/Hydrate Fonn A according to any one of Embodiments 111 -118, or a pharmaceutical composition according to Embodiment 119.

121. The method according to Embodiment 120, wherein the patient has a Z mutation in alpha-1 antitrypsin.

122. The method according to Embodiment 120, wherein the patient has an SZ mutation în alpha-1 antitrypsin.

123. The method according to Embodiment 120, wherein the patient is homozygous for Zmutations in alpha-1 antitrypsin.

124. Use of the Compound 33 MeOHÆEO Solvate/Hydrate Form A according to any one of Embodiments 111-118 în the manufacture of a médicament for treating alpha-1 antitrypsin deficiency.

125. Substantially crystalline Compound 33 Form C.

126. The Compound 33 Fonn C according to Embodiment 125, wherein Compound 33 is substantially pure crystalline Compound 33 Fonn C.

127. The Compound 33 Form C according to Embodiment 125 or Embodiment 126, wherein Compound 33 Form C is characterized by an X-ray powder diffractogram having signais at 9.4 ± 0.2 degrees two-theta and 15.4 ± 0.2 degrees two-theta.

231

128. The Compound 33 Form C according to Embodiment 125 or Embodiment 126, wherein Compound 33 Form C is characterized by an X-ray powder diffractogram having a signal at (a) 9.4 ± 0.2 degrees two-theta and 15.4 ± 0.2 degrees two-theta and (b) 19.0 ± 0.2 degrees two-theta and/or 21.0 ± 0.2 degrees two-theta.

129. The Compound 33 Form C according to Embodiment 125 or Embodiment 126, wherein Compound 33 Form C is characterized by an X-ray powder diffractogram having signais at 9.4 ± 0.2 degrees two-theta, 15.4 ± 0.2 degrees two-theta, 19.0 ± 0.2 degrees two-theta, and 21.0 ± 0.2 degrees two-theta.

130. The Compound 33 Form C according to Embodiment 125 or Embodiment 126, wherein Compound 33 Form C is characterized by an X-ray powder diffractogram having signais at at least four, at least six, or eight two-theta values chosen from 9.4 ± 0.2 degrees two-theta, 15.4 ± 0.2 degrees two-theta, 18.2 ± 0.2 degrees two-theta, 19.0 ± 0.2 degrees two-theta, 19.6 ± 0.2 degrees two-theta, 20.2 ± 0.2 degrees two-theta, 21.0 ± 0.2 degrees two-theta, and 21.5 ± 0.2 degrees two-theta.

131. The Compound 33 Form C according to Embodiment 125 or Embodiment 126, wherein Compound 33 Form C is characterized by an X-ray powder diffractogram substantially similar to FIG. 6A.

132. A pharmaceutical composition comprising the Compound 33 Fonn C according to any one of Embodiments 125-131 and a pharmaceutically acceptable carrier.

133. A method of treating alpha-1 antitrypsin deficiency comprising administering to a patient in need thereof the Compound 33 Form C according to any one of Embodiments 125-131, or a phannaceuticai composition according to Embodiment 132.

134. The method according to Embodiment 133, wherein the patient has a Z mutation in alpha-1 antitrypsin.

135. The method according to Embodiment 133, wherein the patient has an SZ mutation in alpha-1 antitrypsin.

232

136. The method according to Embodiment 133, wherein the patient is homozygous for Zmutations în alpha-1 antitrypsin.

137. Use of the Compound 33 Form C according to any one of Embodiments 125-131 in the manufacture of a médicament for treating alpha-1 antitrypsin detîciency.

138. Substantially crystalline Compound 33 Form D.

139. The Compound 33 Form D according to Embodiment 138, wherein Compound 33 is substantially pure crystalline Compound 33 Form D.

140. The Compound 33 Form D according to Embodiment 138 or Embodiment 139, wherein Compound 33 Form D is characterized by an X-ray powder diffractogram having signais at 14.4 ± 0.2 degrees two-theta and 24.0 ± 0.2 degrees two-theta.

141, The Compound 33 Form D according to Embodiment 138 or Embodiment 139, wherein Compound 33 Form D is characterized by an X-ray powder diffractogram having signais at (a) 14.4 ± 0.2 degrees two-theta and 24.0 ± 0.2 degrees two-theta and (b) 10.4 ± 0.2 degrees twotheta and/or 20.5 ± 0.2 degrees two-theta.

142. The Compound 33 Fonn D according to Embodiment 138 or Embodiment 139, wherein Compound 33 Form D is characterized by an X-ray powder diffractogram having signais ai 10.4 ±0.2 degrees two-theta, 14.4 ± 0.2 degrees two-theta, 20.5 ± 0.2 degrees two-theta, and 24.0 ± 0.2 degrees two-theta.

143. The Compound 33 Form Daccording to Embodiment 138 or Embodiment 139, wherein Compound 33 Form D îs characterized b y an X-ray powder diffractogram having signais at at least four, at least six, at least eight, or at least ten two-theta values chosen from 7.8 ± 0.2 degrees two-theta, 8.2 ± 0.2 degrees two-theta, 8.6 ± 0.2 degrees two-theta, 10.4 ± 0.2 degrees two-theta, 13.7 ± 0.2 degrees two-theta, 14.4 ± 0.2 degrees two-theta, 15.3 ± 0.2 degrees twotheta, 18.6 ± 0.2 degrees two-theta, 18.9 ± 0.2 degrees two-theta, 20.1 ± 0.2 degrees two-theta, 20.5 ± 0.2 degrees two-theta, 21.9 ± 0.2 degrees two-theta, 24.0 ± 0.2 degrees two-theta, and 24.3 ± 0.2 degrees two-theta.

233

144. The Compound 33 Form D according to Embodiment 137 or Embodiment 138, wherein Compound 33 Form D is characterized by an X-ray powder diffractogram substantially similar to FIG. 7A.

145. A pharmaceutical composition comprising the Compound 33 Form D according to any one of Embodiments 138-144 and a pharmaceutically acceptable carrier.

146. A method of treating alpha-1 antitrypsin deficiency comprising administering to a patient in need thereof the Compound 33 Form D according to any one of Embodiments 138-144, or a pharmaceutical composition according to Embodiment 145.

147. The method according to Embodiment 146, wherein the patient has a Z mutation in alpha-1 antitrypsin.

148. The method according to Embodiment 146, wherein the patient has an SZ mutation in alpha-1 antitrypsin.

149. The method according to Embodiment 146, wherein the patient is homozygous for Zmutations in alpha-1 antitrypsin.

150. Use of the Compound 33 Form D according to any one of Embodiments 138-144 in the manufacture of a médicament for treating alpha-1 antitrypsin deficiency.

151. Substantially crystalline Compound 33 Fonn E.

152. The Compound 33 Fonn E according to Embodiment 151, wherein Compound 33 is substantially pure crystalline Compound 33 Form E.

153. The Compound 33 Form E according to Embodiment 151 or Embodiment 152, wherein Compound 33 Fonn E is characterized by an X-ray powder diffractogram having signais at 16.2 ± 0.2 degrees two-theta and 17.9 ± 0.2 degrees two-theta.

154. The Compound 33 Fonn E according to Embodiment 151 or Embodiment 152, wherein Compound 33 Fonn E is characterized by an X-ray powder diffractogram having signais at (a)

234

16.2 ± 0.2 degrees two-theta and 17.9 ± 0.2 degrees two-theta and (b) 12.6 ± 0.2 degrees twotheta and/or 20.7 ± 0.2 degrees two-theta.

155. The Compound 33 Fonn E according to Embodiment 151 or Embodiment 152, wherein Compound 33 Form E is characterized by an X-ray powder diffractogram having signais at 12.6 ± 0.2 degrees two-theta, 16.2 ± 0.2 degrees two-theta, 17.9 ± 0.2 degrees two-theta, and 20.7 ± 0.2 degrees two-theta.

156. The Compound 33 Form E according to Embodiment 151 or Embodiment 152, wherein Compound 33 Form E is characterized by an X-ray powder diffractogram having signais at ai least four, at least six, at least eight, at least ten, or at least twelve two-theta values chosen from 7.9 ± 0.2 degrees two-theta, 11.2 ± 0.2 degrees two-theta, 12.6 ± 0.2 degrees two-theta, 12.8 ± 0.2 degrees two-theta, 13.7 ± 0.2 degrees two-theta, 15.3 ± 0.2 degrees two-theta, 16.2 ± 0.2 degrees two-theta, 17.9 ± 0.2 degrees two-theta, 19.9 ± 0.2 degrees two-theta, 20.7 ± 0.2 degrees two-theta, 21.1 ± 0.2 degrees two-theta, 22.5 ± 0.2 degrees two-theta, 22.8 ± 0.2 degrees twotheta, 24.1 ± 0.2 degrees two-theta, 25.0 ± 0.2 degrees two-theta, 27.0 ± 0.2 degrees two-theta, and 28.9 ± 0.2 degrees two-theta.

157. The Compound 33 Form E according to Embodiment 150 or Embodiment 151, wherein Compound 33 Form E is characterized by an X-ray powder diffractogram substantially similar to FIG. 8A.

158. A pharmaceutical composition comprising the Compound 33 Form E according to any one of Embodiments 151-157 and a phannaceutically acceptable carrier.

159. A method of treating alpha-1 antitrypsin deficiency comprising administering to a patient in need thereof the Compound 33 Fonn E according to any one of Embodiments 151-157, or a pharmaceutical composition according to Embodiment 143.

160. The method according to Embodiment 159, wherein the patient has a Z mutation in alpha-1 antitrypsin.

161. The method according to Embodiment 159, wherein the patient has an SZ mutation in alpha-1 antitrypsin.

235

162. The method according to Embodiment 159, wherein the patient is homozygous for Zmutations in alpha-1 antitrypsin.

163. Use of the Compound 33 Form E according to any one of Embodiments 151-157 in the manufacture of a médicament for treating alpha-1 antitrypsin deficiency.

164. Substantially crystalline Compound 33 Form F.

165. The Compound 33 Fonn F according to Embodiment 164, wherein Compound 33 is substantially pure crystalline Compound 33 Fonn F.

166. The Compound 33 Fonn F according to Embodiment 164 or Embodiment 165, wherein Compound 33 Form F îs characterized by an X-ray powder diffractogram having a signal at one or more two-theta values selected from 8.6 ± 0.2 degrees two-theta, 13.0 ± 0.2 degrees two-theta, and 23.0 ± Ü.2 degrees two-theta.

167. The Compound 33 Form F according to Embodiment 164 or Embodiment 165, wherein Compound 33 Form F is characterized by an X-ray powder diffractogram having signais at 8.6 ± 0.2 degrees two-theta, 13.0 ± 0.2 degrees two-theta, and 23.0 ± 0.2 degrees two-theta.

168. The Compound 33 Fonn F according to Embodiment 151 or Embodiment 152, wherein Compound 33 Fonn F is characterized by an X-ray powder diffractogram having signais at at least four, at least six, at least eight, at least ten, or at least twelve two-theta values chosen from 7.7 ± 0.2 degrees two-theta, 8.6 ± 0.2 degrees two-theta, 11.4 ± 0.2 degrees two-theta, 11.6 ± 0.2 degrees two-theta, 12.2 ± 0.2 degrees two-theta, 13.0 ± 0.2 degrees two-theta, 14.2 ± 0.2 degrees two-theta, 14.9 ± 0.2 degrees two-theta, 17.3 ± 0.2 degrees two-theta, 17.4 ± 0.2 degrees twotheta, 17.8 ± 0.2 degrees two-theta, 18.3 ± 0.2 degrees two-theta, 19.0 ± 0.2 degrees two-theta, 20.4 ± 0.2 degrees two-theta, 21.4 ± 0.2 degrees two-theta, 21.6 ± 0.2 degrees two-theta, 22.6 ± 0.2 degrees two-theta, 22.8 ± 0.2 degrees two-theta, 23.0 ± 0.2 degrees two-theta, 23.3 ± 0.2 degrees two-theta, 24.0 ± 0.2 degrees two-theta, 24.2 ± 0.2 degrees two-theta, 24.9 ± 0.2 degrees two-theta, 25.8 ± 0.2 degrees two-theta, and 26.4 ± 0.2 degrees two-theta.

169. The Compound 33 Form F according to Embodiment 150 or Embodiment 151, wherein Compound 33 Form F is characterized b y an X-ray powder diffractogram substantially similar to FIG. 9A.

236

170. A pharmaceutical composition comprising the Compound 33 Fonn F according to any one of Embodiments 164-169 and a phannaceutically acceptable carrier.

171. A method of treating alpha-1 antitrypsin deficiency comprising administering to a patient in need thereof the Compound 33 Form F according to any one of Embodiments 164-169, or a pharmaceutical composition according to Embodiment 170.

172. The method according to Embodiment 17 i, wherein the patient has a Z mutation in alpha-1 antitrypsin.

173. The method according to Embodiment 171, wherein the patient has an SZ mutation in alpha-1 antitrypsin.

174. The method according to Embodiment 171, wherein the patient is homozygous for Zmutatîons in alpha-1 antitrypsin.

175. Use of the Compound 33 Fonn F according to any one of Embodiments 164-169 in the manufacture of a médicament for treating alpha-1 antitrypsin deficiency.

176. Substantially crystalline Compound 33 Form G.

177. The Compound 33 Form G according to Embodiment 176, wherein Compound 33 is substantially pure crystalline Compound 33 Form G.

178. The Compound 33 Form G according to Embodiment 176 or Embodiment 177, wherein Compound 33 Form G is characterized by an X-ray powder diffractogram having a signal at one or more two-theta values selected ffom 19.8 ± 0.2 degrees two-theta, 20.2 ± 0.2 degrees twotheta, and 20.8 ± 0.2 degrees two-theta.

179. The Compound 33 Form G according to Embodiment 176 or Embodiment 177, wherein

Compound 33 Form G is characterized by an X-ray powder diffractogram signais at 19.8 ± 0.2 degrees two-theta, 20.2 ± 0.2 degrees two-theta, and 20.8 ± 0.2 degrees two-theta.

237

180. The Compound 33 Fonn G according to Embodiment 176 or Embodiment 177, wherein Compound 33 Fonn G is characterized by an X-ray powder diffractogram having signais at at least four, at least six, at least eight, at ieast ten, or at least twelve two-theta values chosen from 9.3 ± 0.2 degrees two-theta, 10.8 ± 0.2 degrees two-theta, 11.5 ± 0.2 degrees two-theta, 12.6 ± 0.2 degrees two-theta, 17.5 ± 0.2 degrees two-theta, 18.4 ± 0.2 degrees two-theta, 19.1 ± 0.2 degrees two-theta, 19.8 ± 0.2 degrees two-theta, 20.2 ± 0.2 degrees two-theta, 20.8 ± 0.2 degrees two-theta, 21.6 ± 0.2 degrees two-theta, 22.6 ± 0.2 degrees two-theta, 23.4 ± 0.2 degrees twotheta, 24.2 ± 0.2 degrees two-theta and 25.5 ± 0.2 degrees two-theta.

181. The Compound 33 Fonn G according to Embodiment 176 or Embodiment 177, wherein Compound 33 Fonn G is characterized by an X-ray powder diffractogram substantially similar to FIG. 10A.

182. A phannaceutical composition comprising the Compound 33 Form G according to any one of Embodiments 176-181 and a pharmaceutically acceptable carrier.

183. A method of treating alpha-1 antitrypsin deficiency comprising administering to a patient in need thereof the Compound 33 Form G according to any one of Embodiments 176-181, or a pharmaceutical composition according to Embodiment 182.

184. The method according to Embodiment 183, wherein the patient has a Z mutation in alpha-1 antitrypsin.

185. The method according to Embodiment 183, wherein the patient has an SZ mutation in alpha-1 antitrypsin.

186. The method according to Embodiment 183, wherein the patient is homozygous for Zmutations in alpha-1 antitrypsin.

187. Use ofthe Compound 33 Form G according to any one of Embodiments 176-181 in the manufacture of a médicament for treating alpha-1 antitrypsin deficiency.

188. Substantially crystalline Compound 33 Fonn H,

238

189. The Compound 33 Fonn H according to Embodiment l 88, wherein Compound 33 is substantially pure crystalline Compound 33 Form H,

190. The Compound 33 Form H according to Embodiment 188 or Embodiment 189, wherein Compound 33 Form H is characterized by an X-ray powder diffractogram having a signal at one or more two-theta values selected from 5.0 ± 0.2 degrees two-theta, 18.3 ± 0.2 degrees two-theta, and 19.5 ± 0.2 degrees two-theta.

191. The Compound 33 Fonn H according to Embodiment 188 or Embodiment 189, wherein Compound 33 Form H is characterized by an X-ray powder diffractogram signais at 5.0 ± 0.2 degrees two-theta, 18.3 ± 0.2 degrees two-theta, and 19.5 ± 0.2 degrees two-theta.

192. The Compound 33 Form H according to Embodiment 188 or Embodiment 189, wherein Compound 33 Fonn H is characterized by an X-ray powder diffractogram having signais at at least four, at least six, at least eight, at least ten, or at least twelve two-theta values chosen from 5.0 ± 0.2 degrees two-theta, 8.8 degrees two-theta, 15.0 degrees two-theta, 17.6 degrees twotheta, 18.3 ± 0.2 degrees two-theta, 18.9 degrees two-theta, 19.5 ± 0.2 degrees two-theta, and 20.7 degrees two-theta.

193. The Compound 33 Form H according to Embodiment 188 or Embodiment 189, wherein Compound 33 Form H is characterized by an X-ray powder diffractogram having signais at 5.0 ± 0.2 degrees two-theta, 8.8 degrees two-theta, 15.0 degrees two-theta, 17.6 degrees two-theta, 18.3 ± 0,2 degrees two-theta, 18.9 degrees two-theta, 19.5 ± 0.2 degrees two-theta, and 20.7 degrees two-theta.

194. The Compound 33 Form H according to Embodiment 188 or Embodiment 189, wherein Compound 33 Form H is characterized by an X-ray powder diffractogram substantially similar to FIG. 11 A.

195. A pharmaceutical composition comprising the Compound 33 Fonn H according to any one of Embodiments 188-194 and a pharmaceutically acceptable carrier.

196. A method of treating alpha-1 antitrypsin deficiency comprising administering to a patient in need thereof the Compound 33 Form H according to any one of Embodiments 188-194, or a pharmaceutical composition according to Embodiment 195.

239

197. The method according to Embodiment 196, wherein the patient has a Z mutation in alpha-1 antitrypsin.

198. The method according to Embodiment 196, wherein the patient has an SZ mutation in alpha-1 antitrypsin.

199. The method according to Embodiment 196, wherein the patient is homozygous for Zmutations in alpha-1 antitrypsin.

200. Use of the Compound 33 Fonn H according to any one of Embodiments 188-194 in the manufacture of a médicament for treating alpha-1 antitrypsin deficiency.

214. Substantially crystalline Compound 33 Form L

215. The Compound 33 Fonn I according to Embodiment 214, wherein Compound 33 is substantially pure crystalline Compound 33 Fonn I.

216. The Compound 33 Form 1 according to Embodiment 214 or Embodiment 215, wherein Compound 33 Form 1 is characterized by an X-ray powder diffractogram having signais at 9.3 ± 0.2 degrees two-theta, 19.0 ± 0.2 degrees two-theta, and 21.0 ± 0.2 degrees two-theta.

217. The Compound 33 Fonn I according to Embodiment 214 or Embodiment 215, wherein Compound 33 Form I is characterized by an X-ray powder diffractogram having signais at at least four, at least five, or at least six two-theta values chosen from 9.3 ± 0.2 degrees two-theta, 15.4 ± 0.2 degrees two-theta, 18.3 ± 0.2 degrees two-theta, 18.6 ± 0.2 degrees two-theta, 19.0 ± 0.2 degrees two-theta, 20.2 ± 0.2 degrees two-theta, and 21.0 ± 0.2 degrees two-theta.

218. The Compound 33 Form I according to Embodiment 214 or Embodiment 215, wherein Compound 33 Form I is characterized by an X-ray powder diffractogram having signais at 9.3 ± 0.2 degrees two-theta, 15.4 ± 0.2 degrees two-theta, 18.3 ± 0.2 degrees two-theta, 18.6 ± 0.2 degrees two-theta, 19.0 ± 0.2 degrees two-theta, 20.2 ± 0.2 degrees two-theta, and 21.0 ± 0.2 degrees two-theta.

240

219. The Compound 33 Form 1 according to Embodiment 214 or Embodiment 215, wherein Compound 33 Form I is characterized by an X-ray powder diffractogram substantially similar to FIG. 12C.

220. A pharmaceutical composition comprising the Compound 33 Fonn I according to any one of Embodiments 214-219 and a pharmaceutically acceptable carrier.

221. A method of treating alpha-1 antitrypsin deficiency comprising administering to a patient in need thereof the Compound 33 Form I according to any one of Embodiments 214-219, or a phannaceutical composition according to Embodiment 220.

222. The method according to Embodiment 221, wherein the patient has a Z mutation in alpha-1 antitrypsin.

223. The method according to Embodiment 221, wherein the patient has an SZ mutation in alpha-1 antitrypsin.

224. The method according to Embodiment 221, wherein the patient is homozygous for Zmutations in alpha-1 antitrypsin.

225. Use of the Compound 33 Fonn I according to any one of Embodiments 214-219 in the manufacture of a médicament for treating alpha-1 antitrypsin deficiency.

226. Substantially crystalline Compound 33 Tetrahydrofuran (THF) Solvaté Form A.

227. The Compound 33 THF Solvaté Form A according to Embodiment 226, wherein Compound 33 is substantially pure crystalline Compound 33 THF Solvaté Fonn A.

228. The Compound 33 THF Solvaté Form A according to Embodiment 226 or Embodiment 227, wherein Compound 33 THF Solvaté Form A is characterized by an X-ray powder diffractogram having a signal ai 8.2 ± 0.2 degrees two-theta and/or 8.5 ± 0.2 degrees two-theta.

229. The Compound 33 THF Solvaté Form A according to Embodiment 226 or Embodiment 227, wherein Compound 33 THF Solvaté Form A is characterized by an X-ray powder

241 diffractogram having a signal at 19.1 ± 0.2 degrees two-theta and/or 19.4 ± 0.2 degrees twotheta.

230. The Compound 33 THF Solvaté Fonn A according to Embodiment 226 or Embodiment

227, wherein Compound 33 THF Solvaté Form A is characterized by an X-ray powder diffractogram having signais at 8.2 ± 0.2 degrees two-theta, 8.5 ± 0.2 degrees two-theta, 19.1 ± 0.2 degrees two-theta, and 19.4 ± 0.2 degrees two-theta.

231. The Compound 33 THF Solvaté Form A according to Embodiment 226 or Embodiment 10 227, wherein Compound 33 THF Solvaté Form A is characterized by an X-ray powder diffractogram having a signal at at least four, at least six, at least eight, or at least ten two-theta values chosen from 8.2 ± 0.2 degrees two-theta, 8.5 ± 0.2 degrees two-theta, 9.5 ± 0.2 degrees two-theta, 11.3 ± 0.2 degrees two-theta, 17.1 ± 0.2 degrees two-theta, 17.8 ± 0.2 degrees twotheta, 19.1 ± 0.2 degrees two-theta, 19.4 ± 0.2 degrees two-theta, 20.5 ± 0.2 degrees two-theta, 15 21.1 ± 0.2 degrees two-theta, 21.2 ± 0.2 degrees two-theta, 21.5 ± 0.2 degrees two-theta, 22.9 ±

0.2 degrees two-theta, and 23.1 ± 0.2 degrees two-theta.

232. The Compound 33 THF Solvaté Form A according to Embodiment 226 or Embodiment

227, wherein Compound 33 THF Solvaté Form A is characterized by an X-ray powder diffractogram substantially similar to FIG. 13A.

233. The Compound 33 THF Solvaté Form A according to Embodiment 226 or Embodiment

227, wherein Compound 33 THF Solvaté Form A is characterized by a orthorhombic crystal

System, a Pca21 space group, and the foliowing unit cell dimensions measured at l()0°K on a 25 Bruker diffractiometer equipped with Cu K_o radiation (λ=1.54178 Â) and a CMOS detector:

a(Â)	25.12± .01
b (Â)	11.98 ± .01
c(Â)	17.7±O.I
a(°)	90
β(°)	90
γ(°)	90
V (Â3)	5327± 30
Z/Z'	4/2

242

234. The Compound 33 THF Solvaté Form A according to any one of Embodiments 226-233, wherein Compound 33 THF Solvaté Fonn A is characterized as having a ^l3C solid state nuclear magnetic résonance (^lîC ssNMR) spectrum with one, two, three, four, five, six, seven, or more peaks selected from 165.8 ± 0.2 ppm, l40.0± 0.2 ppm, 133.9 ± 0.2 ppm, 121.2 ±0.2 ppm, 114.3 ± 0.2 ppm, 96.1 ± 0.2 ppm, 69.0 ± 0.2 ppm, 25.7 ± 0.2 ppm, and 25.3 ± 0.2 ppm.

235. The Compound 33 THF Solvaté Form A according to any one of Embodiments 226-233, wherein Compound 33 THF Solvaté Fonn A is characterized as having a ^l3C ssNMR spectrum substantially similar to FIG. 13B.

236. The Compound 33 THF Solvaté Form A according to any one of Embodiments 226-235, wherein Compound 33 THF Solvaté Fonn A is characterized by a ¹⁹F solid state nuclear magnetic résonance (^l9F ssNMR) spectrum having a peak at -110.5 ± 0.2 ppm and/or -113.0 ± 0.2 ppm.

237. The Compound 33 THF Solvaté Form A according to any one of Embodiments 226-236, wherein Compound 33 THF Solvaté Form A is characterized by a ^l9F ssNMR spectrum substantially similar ίο FIG 13C.

238. A pharmaceutical composition comprising the Compound 33 THF Solvaté Fonn A according to any one of Embodiments 226-237 and a phannaceutically acceptable carrier.

239. A method of treating alpha-1 antitrypsin deficiency comprising administering to a patient in need thereof the Compound 33 THF Solvaté Form A according to any one of Embodiments 201-206, or a pharmaceutical composition according to Embodiment 238.

240. The method according to Embodiment 239, wherein the patient has a Z mutation in alpha-1 antitrypsin.

241. The method according to Embodiment 239, wherein the patient has an SZ mutation in alpha-1 antitrypsin.

242. The method according to Embodiment 239, wherein the patient îs homozygous for Zmutaiions in alpha-1 antitrypsin.

243

243. Use of the Compound 33 THF Solvaté Form A according to any one of Embodiments 226-237 În the manufacture of a médicament for treating alpha-1 antitrypsin deficiency.

244. Substantially crystalline Compound 33 Form J.

245. The Compound 33 Fonn J according to Embodiment 244, wherein Compound 33 is substantially pure crystalline Compound 33 Form J.

246. The Compound 33 Form J according to Embodiment 244 or Embodiment 245, wherein Compound 33 Form J is characterized by an X-ray powder diffractogram having signais at one or more of 6.6 ± 0.2 degrees two-theta, 7.5 ± 0.2 degrees two-theta, and 15.0 ± 0.2 degrees twotheta.

247. The Compound 33 Fonn J according to Embodiment 244 or Embodiment 245, wherein Compound 33 Fonn J is characterized by an X-ray powder diffractogram having signais at 6.6 ± 0.2 degrees two-theta, 7.5 ± 0.2 degrees two-theta, and 15.0 ± 0.2 degrees two-theta.

248. The Compound 33 Form J according to Embodiment 244 or Embodiment 245, wherein Compound 33 Form J is characterized by an X-ray powder diffractogram having (a) signais at 6.6 ± 0.2 degrees two-theta, 7.5 ± 0.2 degrees two-theta, and 15.0 ± 0.2 degrees two-theta; and (b) a signal at at least one, at least two, at least three, at least four, at least six, at least eight, or at least ten two-theta values chosen from 10.3 ± 0.2 degrees two-theta, 15.6 ± 0.2 degrees twotheta, l6.0±0.2 degrees two-theta, 16.8 ± 0.2 degrees two-theta, !7.9±0.2 degrees two-theta, 19.4 ± 0.2 degrees two-theta, 19,9 ± 0.2 degrees two-theta, 20.1 ± 0.2 degrees two-theta, 20.6 ± 0.2 degrees two-theta, 20.8 ± 0.2 degrees two-theta, 21.4 ± 0.2 degrees two-theta, 21.7 ± 0.2 degrees two-theta, and 22.5 ± 0.2 degrees two-theta.

249. The Compound 33 Fonn J according to Embodiment 244 or Embodiment 245, wherein Compound 33 Fonn J is characterized by an X-ray powder diffractogram substantially similar to FIG. 14A.

250. A pharmaceutical composition comprising the Compound 33 Fonn J according to any one of Embodiments 244-249 and a pharmaceutically acceptable carrier.

244

251. A method of treating alpha-1 antitrypsin defïciency comprising administering to a patient in need thereof the Compound 33 Form J according to any one of Embodiments 244-249, or a phanriaceutical composition according to Embodiment 250.

252. The method according to Embodiment 251, wherein the patient has a Z mutation în alpha-1 antitrypsin.

253. The method according to Embodiment 251, wherein the patient has an SZ mutation in alpha-1 antitrypsin.

254. The method according to Embodiment 252, wherein the patient is homozygous for Zmutations in alpha-1 antitrypsin.

255. Use of the Compound 33 Form J according to any one of Embodiments 244-249 in the manufacture of a médicament for treating alpha-1 antitrypsin defïciency.

256. Substantially crystalline Compound 33 Form K.

257. The Compound 33 Form K according to Embodiment 256, wherein Compound 33 is substantially pure crystalline Compound 33 Form K.

258. The Compound 33 Fonn K according to Embodiment 256 or Embodiment 257, wherein Compound 33 Fonn K is characterized by an X-ray powder diffractogram having a signal at 14.5 ± 0.2 degrees two-theta.

259. The Compound 33 Fonn K according to Embodiment 256 or Embodiment 257, wherein Compound 33 Fonn K is characterized by an X-ray powder diffractogram having signais at 14.5 ± 0.2 degrees two-theta and at one or more of 9.7 ± 0.2 degrees two-theta, 19.7 ± 0.2 degrees two-theta, and 20.5 ± 0.2 degrees two-theta.

260. The Compound 33 Fonn K according to Embodiment 256 or Embodiment 257, wherein Compound 33 Fonn K is characterized b y an X-ray powder diffractogram having signais at 9.7 ± 0.2 degrees two-theta, 14.5 ± 0.2 degrees two-theta, 19.7 ± 0.2 degrees two-theta, and 20.5 ± 0.2 degrees two-theta.

245

261. The Compound 33 Form K according to Embodiment 256 or Embodiment 257, wherein Compound 33 Form K is characterized by an X-ray powder diffractogram having (a) signais at signais at 9.7 ± 0.2 degrees two-theta, 14.5 ± 0.2 degrees two-theta, 19.7 ± 0.2 degrees two-theta, and 20.5 ± 0.2 degrees two-theta, and a signal at at least one, at least two, at least three, at least four, at least five, or at least six, two-theta values chosen from 11.2 ± 0.2 degrees two-theta, 14.5 ± 0.2 degrees two-theta, 17.0 ± 0.2 degrees two-theta, 19.1 ± 0.2 degrees two-theta, 19.4 ± 0.2 degrees two-theta, 21.0 ± 0.2 degrees two-theta, and 24.4 ± 0.2 degrees two-theta.

262. The Compound 33 Form K according to Embodiment 256 or Embodiment 257, wherein Compound 33 Form K îs characterized by an X-ray powder diffractogram substantially similar to FIG. 15A.

263. A phannaceutical composition comprising the Compound 33 Form K according to any one of Embodiments 256-262 and a pharmaceutically acceptable carrier.

264. A method of treating alpha- i antitrypsin deficiency comprising administering to a patient in need thereof the Compound 33 Form K according to any one of Embodiments 256-262, or a phannaceutical composition according to Embodiment 263.

265. The method according to Embodiment 264, wherein the patient has a Z mutation in alpha-1 antitrypsin.

266. The method according to Embodiment 264, wherein the patient has an SZ mutation in alpha-1 antitrypsin.

267. The method according to Embodiment 264, wherein the patient is homozygous for Zmutations in alpha-1 antitrypsin.

268. Use of the Compound 33 Form K according to any one of Embodiments 256-262 in the manufacture of a médicament for treating alpha-1 antitrypsin deficiency.

269. Substantially crystalline Compound 33 2-Methyltetrahydrofuran (2-MeTHF) Solvaté

Fonn A.

246

270, The Compound 33 2-MeTHF Solvaté Fonn A according to Embodiment 269, wherein Compound 33 is substantially pure crystalline Compound 33 2-MeTHF Solvaté Form A.

271. The Compound 33 2-MeTHF Solvaté Fonn A according to Embodiment 269 or Embodiment 270, wherein Compound 33 2-MeTHF Solvaté Fonn A is characterized by an Xray powder diffractogram having a signal a signal ai 18.1 ±0.2 degrees two-theta, 19.0 ± 0.2 degrees two-theta, and/or 21.3 ± 0.2 degrees two-theta.

272. The Compound 33 2-MeTHF Solvaté Form A according to Embodiment 269 or Embodiment 270, wherein Compound 33 2-MeTHF Solvaté Fonn A is characterized by an Xray powder diffractogram having having (a) signais ai 18.1 ± 0.2 degrees two-theta, 19.0 ± 0.2 degrees two-theta, and 21.3 ± 0.2 degrees two-theta; and (b) a signal at at least one, at least two, at least three, or at four two-theta values chosen from 13.8 ± 0.2 degrees two-theta, 18.7 ± 0.2 degrees two-theta, 20.0 + 0.2 degrees two-theta, and 20.8 ± 0.2 degrees two-theta.

273. The Compound 33 2-MeTHF Solvaté Fonn A according to Embodiment 269 or Embodiment 270, wherein Compound 33 2-MeTHF Solvaté Form A is characterized by an Xray powder diffractogram substantially similar to FIG. 16A.

274. A phannaceutîcal composition comprising the Compound 33 2-MeTHF Solvaté Fonn A according to any one of Embodiments 256-262 and a phannaceutically acceptable carrier.

275. A method of treating alpha-1 antitrypsin deficiency comprising administering to a patient in need thereof the Compound 33 2-MeTHF Solvaté Form A according to any one of Embodiments 269-273, or a phannaceutîcal composition according to Embodiment 274.

276. The method according to Embodiment 275, wherein the patient has a Z mutation in alpha-1 antitrypsin.

277. The method according to Embodiment 275, wherein the patient has an SZ mutation in alpha-1 antitrypsin,

278. The method according to Embodiment 275, wherein the patient is homozygous for Zmutatîons in alpha-1 antitrypsin.

247

279. Use of the Compound 33 2-MeTHF Solvaté Form A according to any one of Embodiments 269-273 in the manufacture of a médicament for treating alpha-1 antitrypsin défi ci en cy.

280. Substantially crystalline Compound 33 Form L.

281. The Compound 33 Form L according to Embodiment 280, wherein Compound 33 is substantially pure crystalline Compound 33 Form L.

282. The Compound 33 Form L according to Embodiment 280 or Embodiment 281, wherein Compound 33 Form L is characterized by an X-ray powder diffractogram having a signal at 14.5 ± 0.2 degrees two-theta.

283. The Compound 33 Form L according to Embodiment 280 or Embodiment 281, wherein Compound 33 Form L is characterized by an X-ray powder diffractogram having signais at one or more of 14.5 ± 0.2 degrees two-theta, 14.6 + 0.2 degrees two-theta, 16.3 ± 0.2 degrees twotheta, and 17.3 ± 0.2 degrees two-theta.

284. The Compound 33 Form L according to Embodiment 280 or Embodiment 281, wherein Compound 33 Form L is characterized b y an X-ray powder diffractogram having signais at 14.5 ± 0.2 degrees two-theta, 14.6 + 0.2 degrees two-theta, 16.3 ± 0.2 degrees two-theta, and 17.3 ± 0.2 degrees two-theta.

285. The Compound 33 Form L according to Embodiment 280 or Embodiment 281, wherein Compound 33 Form L is characterized by an X-ray powder diffractogram having (a) signais at 14.5 ± 0.2 degrees two-theta, 14.6 ± 0.2 degrees two-theta, 16.3 ± 0.2 degrees two-theta, and 17.3 ± 0.2 degrees two-theta; and (b) a signal at at least one, at least two, at least four, at least six, at least eight, or at least ten two-theta values chosen from 7.0 ± 0.2 degrees two-theta, 8.8 ± 0.2 degrees two-theta, 9.9 ± 0.2 degrees two-theta, 13.7 ± 0.2 degrees two-theta, 17.6 ± 0.2 degrees two-theta, 17.9 + 0.2 degrees two-theta, 18.6±0.2 degrees two-theta, 18.8 ± 0.2 degrees two-theta, 19.7 ± 0.2 degrees two-theta, 20.2 ± 0.2 degrees two-theta, 20.4 ± 0.2 degrees twotheta, 20.7 + 0.2 degrees two-theta, 20.9 + 0.2 degrees two-theta, 21.0 + 0.2 degrees two-theta, 21.9 ± 0.2 degrees two-theta, 22.2 + 0.2 degrees two-theta, 23.1 ±0.2 degrees two-theta, 23.6 ± 0.2 degrees two-theta, 27.1 ±0.2 degrees two-theta, 28.6 + 0.2 degrees two-theta, and 3 1.7 ± 0.2 degrees two-theta.

248

286. The Compound 33 Form L according to Embodiment 280 or Embodiment 281, wherein Compound 33 Form L is characterized by an X-ray powder diffractogram substantially similar to FIG. 17A.

287. A pharmaceutical composition comprising the Compound 33 Fonn L according to any one of Embodiments 281-286 and a pharmaceutically acceptable carrier.

288. A method of treating alpha-1 antitrypsin defïciency comprising administering to a patient in need thereof the Compound 33 Form L according to any one of Embodiments 281-286, or a phannaceutical composition according to Embodiment 287.

289. The method according to Embodiment 288, wherein the patient has a Z mutation in alpha-1 antitrypsin.

290. The method according to Embodiment 288, wherein the patient has an SZ mutation in alpha-1 antitrypsin.

291. The method according to Embodiment 288, wherein the patient is homozygous for Zmutations in alpha-1 antitrypsin.

292. Use ofthe Compound 33 Form L according to any one of Embodiments 281-286 in the manufacture of a médicament for treating alpha-1 antitrypsin defïciency.

293. Substantially crystalline Compound 33 Fonn M.

294. The Compound 33 Form M according to Embodiment 293, wherein Compound 33 is substantially pure crystalline Compound 33 Fonn M.

295. The Compound 33 Form M according to Embodiment 292 or Embodiment 293, wherein Compound 33 Form M is characterized by an X-ray powder diffractogram having a signal at one or more of 18.3 ± 0.2 degrees two-theta, 18.9 ± 0.2 degrees two-theta, and 21.2 ± 0.2 degrees two-theta.

249

296, The Compound 33 Fonn M according to Embodiment 292 or Embodiment 293, wherein Compound 33 Form M is characterized by an X-ray powder diffractogram having signais at lS,3 ± 0.2 degrees two-theta, 18.9 ± 0.2 degrees two-theta, and 21.2 ± 0.2 degrees two-theta.

297. The Compound 33 Form M according to Embodiment 292 or Embodiment 293, wherein Compound 33 Form M is characterized by an X-ray powder diffractogram having (a) signais at of 18.3 ± 0.2 degrees two-theta, 18.9 ± 0.2 degrees two-theta, and 21.2 ± 0.2 degrees two-theta; and (b) a signal at at least one, at least two, at least three, or at least four two-theta values chosen from 7.0 ± 0.2 degrees two-theta, 8.4 ± 0.2 degrees two-theta, 11.3 ± 0.2 degrees two-theta, 13.8 ± 0.2 degrees two-theta, 16.0 ± 0.2 degrees two-theta, 17.2 ± 0.2 degrees two-theta, 9.4 ± 0.2 degrees two-theta, 20.6 ± 0.2 degrees two-theta, and 21.7 ± 0.2 degrees two-theta.

29S. The Compound 33 Fonn M according to Embodiment 292 or Embodiment 293, wherein Compound 33 Fonn M is characterized by an X-ray powder diffractogram substantially similar to FIG. 18A

299. A pharmaceutical composition comprising the Compound 33 Fonn M according to any one of Embodiments 293-298 and a pharmaceutically acceptable carrier.

300. A method of treating alpha-1 antitrypsin deficiency comprising administering to a patient in need thereof the Compound 33 Form M according to any one of Embodiments 293-298, or a phannaceutical composition according to Embodiment 299.

301. The method according to Embodiment 300, wherein the patient has a Z mutation in alpha-1 antitrypsin.

302. The method according to Embodiment 300, wherein the patient has an SZ mutation în alpha-1 antitrypsin.

303. The method according to Embodiment 300, wherein the patient is homozygous for Zmutations in alpha-1 antitrypsin.

304. Use of the Compound 33 Form M according to any one of Embodiments 293-298 in the manufacture of a médicament for treating alpha-1 antitrypsin deficiency.

250

3Ü5. Substantially crystalline Compound 33 Fonn N.

306. The Compound 33 Fonn N according to Embodiment 305, wherein Compound 33 is substantially pure crystalline Compound 33 Fonn N.

307. The Compound 33 Form N according to Embodiment 305 or Embodiment 306, wherein Compound 33 Fonn N is characterized by an X-ray powder diffractogram having a signal at one or more of 13.0 ± 0.2 degrees two-theta, 14.3 ± 0.2 degrees two-theta, and 18.2 ± 0.2 degrees two-theta.

308. The Compound 33 Fonn N according to Embodiment 305 or Embodiment 306, wherein Compound 33 Fonn N îs characterized by an X-ray powder diffractogram having signais at 13.0 ± 0.2 degrees two-theta, 14.3 ± 0.2 degrees two-theta, and 18.2 ± 0.2 degrees two-theta.

309. The Compound 33 Form N according to Embodiment 305 or Embodiment 306, wherein Compound 33 Form N is characterized by an X-ray powder diffractogram having (a) signais at 13.0 ± 0.2 degrees two-theta, 14.3 ± 0.2 degrees two-theta, and 18.2 ± 0.2 degrees two-theta; and (b) a signal at at least two, at least four, at least six, at least eight, or at least ten two-theta values chosen from 4.2 ± 0.2 degrees two-theta, 8.8 ± 0.2 degrees two-theta, 11.7 ± 0.2 degrees twotheta, 12.3 ± 0.2 degrees two-theta, 12.6 ± 0.2 degrees two-theta, 15.6 ± 0.2 degrees two-theta, 17.1 ± 0.2 degrees two-theta, 17.6 ± 0.2 degrees two-theta, 18.7 ± 0.2 degrees two-theta, 19.2 ± 0.2 degrees two-theta, 19.6 ± 0.2 degrees two-theta, 20.5 ± 0.2 degrees two-theta, 21.5 ± 0.2 degrees two-theta, 21.8 ± 0.2 degrees two-theta, 22.2 ± 0.2 degrees two-theta, 22.7 ± 0.2 degrees two-theta, 23.1 ± 0.2 degrees two-theta, 24.0 ± 0.2 degrees two-theta, 25.6 ± 0.2 degrees twotheta, 26.1 ± 0.2 degrees two-theta, 26,8 ± 0.2 degrees two-theta, 28.0 ± 0.2 degrees two-theta, and 28.4 ± 0.2 degrees two-theta.

310. The Compound 33 Form N according to Embodiment 305 or Embodiment 306, wherein Compound 33 Form N is characterized by an X-ray powder diffractogram substantially similar to FIG. 19A

311. A pharmaceutical composition comprising the Compound 33 Form N according to any one of Embodiments 305-309 and a phannaceutically acceptable carrier.

251

312. A method of treating alpha-1 antitrypsin deficiency comprising administering to a patient in need thereof the Compound 33 Form N according to any one of Embodiments 305-310, or a pharmaceutical composition according to Embodiment 311.

313. The method according to Embodiment 312, wherein the patient has a Z mutation in alpha-1 antitrypsin.

314. The method according to Embodiment 312, wherein the patient has an SZ mutation in alpha-1 antitrypsin.

315. The method according to Embodiment 312, wherein the patient is homozygous for Zmutations în alpha-1 antitrypsin.

316. Use of the Compound 33 Form N according to any one of Embodiments 305-310 in the manufacture of a médicament for treating alpha-1 antitrypsin deficiency.

317. Substantially crystalline Compound 33 Form O.

318. The Compound 33 Form N according to Embodiment 317, wherein Compound 33 is 20 substantially pure crystalline Compound 33 Form O.

319. The Compound 33 Form O according to Embodiment 317 or Embodiment 318, wherein Compound 33 Fonn O is characterized by an X-ray powder diffractogram having a signal at one or more of 7.0 ± 0.2 degrees two-theta, 10.4 ± 0.2 degrees two-theta, 17.4 ± 0.2 degrees two25 thêta, and 21.2 ± 0.2 degrees two-theta.

320. The Compound 33 Fonn O according to Embodiment 317 or Embodiment 318, wherein Compound 33 Form O is characterized by an X-ray powder diffractogram having signais at 7.0 ± 0.2 degrees two-theta, 10.4 ± 0.2 degrees two-theta, 17.4 ± 0.2 degrees two-theta, and 21.2 ± 0.2 30 degrees two-theta.

321. The Compound 33 Form O according to Embodiment 317 or Embodiment 3 18, wherein Compound 33 Fonn O is characterized by an X-ray powder having (a) diffractogram having signais at 7.0 ± 0.2 degrees two-theta, 10.4 ± 0.2 degrees two-theta, 17.4 ± 0.2 degrees two-theta, 35 and 21.2 ± 0.2 degrees two-theta; and (b) a signal at at least one, at least two, at least four, or at 252 least six two-theta values chosen from 8.3 ± 0.2 degrees two-theta, 8.8 ± 0.2 degrees two-theta, 15.5 ± 0.2 degrees two-theta, 16.6 ± 0.2 degrees two-theta, 16.9 ± 0.2 degrees two-theta, 18.8 ± 0.2 degrees two-theta, 19.5 ± 0.2 degrees two-theta, 20.4 ± 0.2 degrees two-theta, 21.6 ± 0.2 degrees two-theta, 22.3 ± 0.2 degrees two-theta, 22.9 ± 0.2 degrees two-theta, and 23.3 ± 0.2 degrees two-theta.

322. The Compound 33 Form O according to Embodiment 317 or Embodiment 318, wherein Compound 33 Fonn O is characterized by an X-ray powder diffractogram substantially similar to FIG. 20A

323. A pharmaceutical composition comprising the Compound 33 Fonn O according to any one of Embodiments 317-322 and a phannaceutically acceptable carrier.

324. A method of treating alpha-1 antitrypsin deficiency comprising administering to a patient in need thereof the Compound 33 Form O according to any one of Embodiments 317-322, or a phannaceutical composition according to Embodiment 323.

325. The method according to Embodiment 324, wherein the patient has a Z mutation m alpha-1 antitrypsin.

326. The method according to Embodiment 324, wherein the patient has an SZ mutation in alpha-1 antitrypsin.

327. The method according to Embodiment 326, wherein the patient is homozygous for Zmutations in alpha-1 antitrypsin.

328. Use of the Compound 33 Form O according to any one of Embodiments 305-309 in the manufacture of a médicament for treating alpha-1 antitrypsin deficiency.

329. Substantially crystalline Compound 33 Potassium Sait Form A.

330. The Compound 33 Potassium Sait Form A according to Embodiment 329, wherein Compound 33 is substantially pure crystalline Compound 33 Potassium Sait Fonn A,

253

l. The Compound 33 Potassium Sait Fonn A according to Embodiment 329 or Embodiment 330, wherein Compound 33 Potassium Sait Fonn A is characterized by an X-ray powder diffractogram having a signal at one or more of 11.7 ± 0.2 degrees two-theta. 18.0 ± 0.2 degrees two-theta, and 20.7 ±0.2 degrees two-theta.

332. The Compound 33 Potassium Sait Fonn A according to Embodiment 317 or Embodiment 318, wherein Compound 33 Potassium Sait Fonn A is characterized by an X-ray powder diffractogram having signais at 11.7 ± 0.2 degrees two-theta, 18.0 ± 0.2 degrees two-theta, and 20.7 ± 0.2 degrees two-theta.

333. The Compound 33 Potassium Sait Fonn A according to Embodiment 317 or Embodiment 318, wherein Compound 33 Potassium Sait Fonn A is characterized by an X-ray powder diffractogram substantially similarto FIG. 21A.

334. A pharmaceutical composition comprising the Compound 33 Potassium Sait Fonn A according to any one of Embodiments 329-333 and a pharmaceutically acceptable carrier.

335. A method of treating alpha-I antitrypsin deficiency comprising administering to a patient in need thereof the Compound 33 Potassium Sait Fonn A according to any one of Embodiments 329-333, or a phannaceutical composition according to Embodiment 334.

336. The method according to Embodiment 335, wherein the patient has a Z mutation in alpha-1 antitrypsin.

337. The method according to Embodiment 335, wherein the patient has an SZ mutation in alpha-1 antitrypsin.

338. The method according to Embodiment 335, wherein the patient is homozygous for Zmutations in alpha-1 antitrypsin.

339. Use ofthe Compound 33 Potassium Sait Form A according to any one of Embodiments 329-333 in the manufacture of a médicament for treating alpha-1 antitrypsin deficiency.

340. Substantially crystalline Compound 33 Potassium Sait Form B.

254

341. The Compound 33 Potassium Sait Form B according to Embodiment 340, wherein Compound 33 is substantially pure crystalline Compound 33 Potassium Sait Form B.

342. The Compound 33 Potassium Sait Form B according to Embodiment 340 or Embodiment 341, wherein Compound 33 Potassium Sait Form B is characterized by an X-ray powder diffractogram having a signal at one or more of 9.1 ± 0.2 degrees two-theta, 13.7 ± 0.2 degrees two-theta, 15.3 ± 0.2 degrees two-theta, 17.5 ± 0.2 degrees two-theta, and 21.7 ± 0.2 degrees two-theta.

343. The Compound 33 Potassium Sait Form B according to Embodiment 340 or Embodiment 341, wherein Compound 33 Potassium Sait Fonn B is characterized by an X-ray powder diffractogram having a signal at two or more of 9.1 ± 0.2 degrees two-theta, 13.7 ± 0.2 degrees two-theta, 1 5.3 ± 0.2 degrees two-theta, 17.5 ± 0.2 degrees two-theta, and 21.7 ± 0.2 degrees two-theta.

344. The Compound 33 Potassium Sait Form B according to Embodiment 340 or Embodiment 341, wherein Compound 33 Potassium Sait Form B is characterized by an X-ray powder diffractogram having a signal at three or more of 9.1 ± 0.2 degrees two-theta, 13.7 ± 0.2 degrees two-theta, 15.3 ± 0.2 degrees two-theta, 17.5 ± 0.2 degrees two-theta, and 21.7 ± 0.2 degrees two-theta.

345. The Compound 33 Potassium Sait Form B according to Embodiment 340 or Embodiment 341, wherein Compound 33 Potassium Sait Form B is characterized by an X-ray powder diffractogram having signais at 9.1 ± 0.2 degrees two-theta, 13.7 ± 0.2 degrees two-theta, 15.3 ± 0.2 degrees two-theta, 17.5 ± 0.2 degrees two-theta, and 21.7 ± 0.2 degrees two-theta.

346. The Compound 33 Potassium Sait Form B according to Embodiment 340 or Embodiment 341, wherein Compound 33 Potassium Sait Form B is characterized by an X-ray powder diffractogram having (a) signais at three or more of 9.1 ± 0.2 degrees two-theta, 13.7 ± 0.2 degrees two-theta, 15.3 ± 0.2 degrees two-theta, 17.5 ± 0.2 degrees two-theta, and 21.7 ± 0.2 degrees two-theta; and (b) a signal at at least one, at least two, or at least three two-theta values chosen from 6.9 ± 0.2 degrees two-theta, 10.8 ± 0.2 degrees two-theta, 20.0 ± 0.2 degrees twotheta, and 20.6 ± 0.2 degrees two-theta.

255

347. The Compound 33 Potassium Sait Fonn B according to Embodiment 340 or Embodiment 341, wherein Compound 33 Potassium Sait Fonn B is characterized by an X-ray powder diffractogram substantially similar to FIG. 22A.

348. A pharmaceutical composition comprising the Compound 33 Potassium Sait Fonn B according to any one of Embodiments 340-347 and a phannaceutically acceptable carrier.

349. A method of treating alpha-1 antitrypsin deficiency comprising administering to a patient in need thereof the Compound 33 Potassium Sait Form B according to any one of Embodiments 340-347, or a pharmaceutical composition according to Embodiment 348.

350. The method according to Embodiment 349, wherein the patient has a Z mutation in alpha-l antitrypsin.

351. The method according to Embodiment 349, wherein the patient has an SZ mutation in alpha-1 antitrypsin.

352. The method according to Embodiment 349, wherein the patient is homozygous for Zmutations in alpha-1 antitrypsin.

353. Use of the Compound 33 Potassium Sait Form B according to any one of Embodiments 340-347 in the manufacture of a médicament for treating alpha-1 antitrypsin deficiency.

354. Substantially crystalline Compound 33 Potassium Sait Fonn C.

355. The Compound 33 Potassium Sait Form C according to Embodiment 354, wherein Compound 33 is substantially pure crystalline Compound 33 Potassium Sait Fonn C.

356. The Compound 33 Potassium Sait Form C according to Embodiment 354 or Embodiment 355, wherein Compound 33 Potassium Sait Form C is characterized by an X-ray powder diffractogram having signais at 16.8 ± 0.2 degrees two-theta and 19.3 ± 0.2 degrees two-theta.

357. The Compound 33 Potassium Sait Form C according to Embodiment 354 or Embodiment

355, wherein Compound 33 Potassium Sait Fonn C is characterized by an X-ray powder diffractogram having signais at (a) 16.8 ± 0.2 degrees two-theta and 19.3 ± 0.2 degrees two-theta 256 and (b) 6.7 ± 0.2 degrees two-theta, and/or 10.5 ± 0.2 degrees two-theta. In some Embodiments, Compound 33 Potassium Sait Fonn C is characterized by an X-ray powder diffractogram having a signal at 6.7 ± 0.2 degrees two-theta, 10.5 ± 0.2 degrees two-theta. 16.8 ± 0.2 degrees twotheta, and 19.3 ± 0.2 degrees two-theta.

358. The Compound 33 Potassium Sait Fonn C according to Embodiment 354 or Embodiment 355, wherein Compound 33 Potassium Sait Fonn C is characterized by an X-ray powder diffractogram substantially similar to FIG. 23A.

359. A pharmaceutical composition comprising the Compound 33 Potassium Sait Fonn C according to any one of Embodiments 354-358 and a pharmaceutically acceptable carrier.

360. A method of treating alpha-1 antitrypsin defïciency comprising administering to a patient in need thereof the Compound 33 Potassium Sait Form B according to any one of Embodiments 15 354-358, or a phannaceutical composition according to Embodiment 359.

361. The method according to Embodiment 360, wherein the patient has a Z mutation in alpha-1 antitrypsin.

362. The method according to Embodiment 360, wherein the patient has an SZ mutation in alpha-1 antitrypsin.

363. The method according to Embodiment 360, wherein the patient is homozygous for Zmutations in alpha-1 antitrypsin.

364. Use of the Compound 33 Potassium Sait Form C according to any one of Embodiments 354-358 in the manufacture of a médicament for treating alpha-1 antitrypsin defïciency.

365-370. (omitted)

371. A method for preparing the compound 4-(5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-1//pyrrolo[2,3-f]indazoi-7-yl]benzoic acid, the method comprising:

(a) contacting methyl 4-(5-(4-fluorophenyl)-l-pivaloyl-6-(tetrahydro-2H-pyran-4-yl)-l,5dihydropyrrolo[2,3-f]indazol-7-yl)benzoate with a first organic solvent and a first base to form a 35 first reaction mixture;

257 (b) adding water and a first acid to the first reaction mixture;

(c) îsolating an organic portion from step (b), adding an alcohol and optionally adding water to the organic portion, and concentrating the mixture by distillation; and (d) isolating the compound 4-[5-(4-fiuorophenyl)-6-tetrahydropyran-4-yl-l/f-pyrrolo[2,3f]indazol-7-yl]benzoic acid from the mixture from step (c) and drying the material to remove ail water content.

372. The method of Embodiment 371, wherein step (a) comprises heatîng methyl 4-(5-(4fluorophenyl)-l-pivaloyl-6-(tetrahydro-2H-pyran-4-yl)-l,5-dihydropyrrolo[2,3-f]indazol-7yl)benzoate with the first organic solvent and the first base to about 50-65 °C.

373. The method of Embodiment 372, wherein step (a) comprises heatîng methyl 4-(5-(4fluorophenyl)-l-pivaloyl-6-(tetrahydro-2H-pyran-4-yl)-l,5-dihydropyrrolo[2,3-f)indazol-7yl)benzoate with the first organic solvent and the first base to about 55-60 °C.

374. The method of Embodiment 373, wherein step (a) comprises heatîng methyl 4-(5-(4fluoro phenyl)-1 -pivaloyl-6-(tetrahydro-2H-pyran-4-yl)-l ,5-dîhydropyrrolo[2,3-f]indazol-7yl)benzoate with the first organic solvent and the first base to about 58 °C.

375. The method of any one of Embodiments 371-374, wherein the first organic solvent is selected from THF, 2-MeTHF, EtOH, MeOH, and IPA.

376. The method of Embodiment 375, wherein the first organic solvent îs THF.

377. The method of any one of Embodiments 371-376, wherein the first base is selected from

LÎOH, NaOH, and KOH.

378. The method of Embodiment 377, wherein the first base is NaOH.

379. The method ofanyone of Embodiments 371-378, wherein step (b) comprises adding water and the first acid to the first reaction mixture at about 15-25 °C.

380. The method of Embodiment 379, wherein step (b) comprises adding water and the first acid to the first reaction mixture at about 20 °C.

381. The method of any one of Embodiments 371-380, wherein step (b) further comprises adding a second organic solvent to the first reaction mixture.

258

382. The method of Embodiment 381, wherein the second organic solvent is 2-MeTHF.

383 The method of any one of Embodiments 371-382, wherein step (c) comprises washing the organic portion with a NaCl aqueous solution prior to adding alcohol and/or water.

384. The method of any one of Embodiments 371-383, wherein the first acid is an organic acid or a strong acid.

385. The method of Embodiment 384, wherein the first acid is acetic acid or HCl.

386. The method of Embodiment 385, wherein the first acid is acetic acid.

387. The method of any one of Embodiments 371-386, wherein step (c) comprises 2 to 10 cycles of adding an alcohol, optionally adding water, and concentrating the mixture b y distillation.

388. The method of any one of Embodiments 371-387, wherein step (c) comprises concentrating the mixture by distillation at about 20-40 °C.

389. The method of any one of Embodiments 371-388, wherein the alcohol is selected from EtOH, MeOH, IPA, TBA, and n-butanol.

390. The method of Embodiment 389, wherein the alcohol is EtOH.

391. The method of any one of Embodiments 371-390, wherein step (d) comprises fîltering the mixture from step (c) to form a wet cake and drying the wet cake.

392. The method of Embodiment 391, wherein the drying comprises drying the wet cake under vacuum at about 60-70 °C.

393. The method of Embodiment 392, wherein the wet cake is dried at about 66 °C.

394. The method of any one of Embodiments 371-393, wherein the method further comprises reacting l-(5-(4-fluorophenyl)-7-iodo-6-(tetrahydro-2H-pyran-4-yI)pyrrolo[2,3-f]indazol-l(5H)yl)-2,2-dimethylpropan-l-one with 4-(methoxycarbonyl)phenyI)boronic acid to fonn methyl 4(5-(4-fluorophenyl)-l-pivaloyI-6-(tetrahydro-2H-pyran-4-yI)-l,5-dihydropyrrolo[2,3-f]indazol7-yl) benzoate.

259

395. The method of Embodiment 394, wherein reacting l-(5-(4-fluorophenyl)-7-iodo-6(tetrahydro-2H-pyran-4-yl)pyirolo[2,3-f]indazol-l(5H)-yl)-2,2“dimethylpropan-1 -one with 4(methoxycarbonyl)phenyl)boronîc acid to fonn methyl 4-(5-(4-fluorophenyl)-l-pivaloyl-6(tetrahydro-2/f-pyran-4-yl)-l,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoate takes place at about 60-70 °C.

396. The method of Embodiment 395, wherein reacting l-(5-(4-fluorophenyl)-7-iodo-6(tetrahydro-2H-pyran-4-yl)pynrolo[2,3-f|indazol-l(5H)-yI)-2,2-dimethylpropan-l-one with 4(methoxycarbonyl)phenyl)boronic acid to form methyl 4-(5-(4-fluorophenyl)-l-pivaloyl-6(tetrahydro-2//-pyran-4-yl)-l,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoate takes place at about 65 °C.

397. The method of any one of Embodiments 394-396, wherein reacting 1-(5-(4fluorophenyl)-7-iodo-6-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,3-f]indazol-l(5H)-yl)-2,2dimethylpropan-1-one with 4-(methoxycarbonyl)phenyl)boronic acid to fonn methyl 4-(5-(4fluoroplienyl)-I-pivaloyl-6-(tetrahydro-2/7-pyran-4-yl)-l,5-dihydropyrrolo[2,3-f]indazol-7yl)benzoate takes place in the presence of a first catalyst, triethylamine, water, a third organic solvent, and a second base.

398. The method of Embodiment 397, wherein the first catalyst is selected from PCy₃P(tBu)₃, DavePhos, SPhos Pd(PPh₃)₂Cl₂, Xphos, CataCXium; Pd(AmPhos)Cl₂, RuPhos, Pd(dippf)CI₂. Pd(dtbpf)Cl₂. Pd(DPEPhos)Cl₂, Pd(dppf)Cl₂*CH₂Cl₂, Pd(Xantphos)Cl₂, and Pd(dppb)Cl₂.

399. The method of Embodiment 39S, wherein the first catalyst is selected Pd(dppf)Cl₂-CH₂Cl₂.

400. The method of any one of Embodiments 397-399, wherein the third organic solvent is selected from 1,4-dioxane, THF, 2-MeTHF, TPA, toluene, ACN, DMSO, EtOH.

401. The method of Embodiment 400, wherein the third organic solvent is THF.

402. The method of any one of Embodiments 397-401, wherein the second base is selected from K₂CO₃, Na₂CO₃, and K₃PO₄.

403. The method of Embodiment 402, wherein the second base is K.₂CO₃.

404. The method of any one of Embodiments 397-403, further comprising removing aryl dimer impurities by charging methyl 4-(5-(4-fluorophenyl)-l-pivaloyl-6-(tetrahydro-2H-pyran-4260 yl)-l,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoate with THF and heating the mixture; adding EtOH to the mixture to form a slurry; stirring the slurry; cooling the slurry and filtering the slurry to fonn a wet cake; and rinsing and drying the wet cake.

405. The method of any one Embodiments 394-404, wherein the method further comprises reacting l -(5-(4-fluorophenyî)-6-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,3-f]indazol-1 (5Æ)-yl)-2,2dimethylpropan-l-one with A-iodosuccinimide to form l-(5-(4-fluorophenyl)-7-iodo-6(tetrahydro-2H-pyran-4-yl)pyrrolo[2,3-f]indazol-l(5H)-yl)-2,2-dimethylpropan-I-one.

406. The method of Embodiment 405, wherein reacting l -(5-(4-fluorophenyl)-6-(tetrahydro227-pyran-4-yl)pyrrolo[2,3-f]îndazol-1 (5/F)-yl)-2,2-dimethyipropan-l -one with Niodosuccinimide to form l-(5-(4-fluorophenyl)-7-iodo-6-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,3f]indazol-l(5H)-yl)-2,2-dimethylpropan-l-one takes place at about -5.0 to 0 °C for about 20-45 minutes.

407. The method of Embodiment 405, wherein reacting l -(5-(4-fluorophenyl)-6-(tetrahydro2/f-pyran-4-yl)pyrrolo[2,3-f]indazol-I(5A)-yl)-2,2-dimethylpropan-l-one with Niodosuccinimide to form l-(5-(4-fluorophenyI)-7-iodo-6-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,3f]indazol-l(5H)-yI)-2,2-dimethylpropan-l-one takes place at about -5.0 °C for about 30 minutes.

408. The method of any one of Embodiments 405-407, wherein reacting l -(5-(4- fhLOrophenyl)-6-(tetrahydro-2/Apyran-4-yI)pyrrolo[2,3-t]indazol-l(5//)-yl)-2,2-dimethylpropanl-one with A-iodosuccinimide to form l-(5-(4-fluorophenyl)-7-iodo-6-(tetrahydro-2H-pyran-4yl)pyrrolo[2,3-f]indazol-l(5H)-yl)-2,2-dimethylpropan-l-one takes place in the presence of a fourth organic solvent selected from THF, MeTHF, ACN, EtOAc, DMF, and DCM.

409. The method of Embodiment 408, wherein the fourth organic solvent is DCM.

410. The method of any one of Embodiments 405-409, wherein the method further comprises reacting 5-(4-fluorophenyl)-6-(tetrahydro-2A-pyran-4-yl)-l,5-dihydropynOlo[2,3-f]indazole with trimethylacetyl chloride to form I-(5-(4-fluorophenyl)-6-(tetrahydro-2/Apyran-4yl)pyirolo[2,3-f]indazol-l (577)-yl)-2,2-dimethyIpropan-1 -one.

411. The method of Embodiment 410, wherein reacting 5-(4-fluorophenyl)-6-(tetrahydro-2Apyran-4-yl)-l,5-dihydropyrrolo[2,3-f]indazole with trimethylacetyl chloride to form 1-(5-(4fluorophenyl)-6-(tetrahydro-2H-pyran-4-yI)pyrrolo[2,3-f]indazol-l(5A)-yl)-2,2-dimethylpropan1 -one takes place at about -6 to 0 °C for about an hour.

261

412. The method of anyone of Embodiments 410 and 411, wherein reacting 5-(4fluorophenyI)-6-(tetrahydro-2/7-pyran-4-yl)-1,5-dihydropyrrolo[2,3-f]indazole with trimethylacetyl chloride to fonn l-(5-(4-fluorophenyl)-6-(tetrahydro-2Z/-pyran-4-yl)pyrrolo[2,3f]indazol-l(5//)-yl)-2,2-dimethylpropan-l-one takes place in the presence of a fifth organic solvent and a third base.

413. The method of Embodiment 412, wherein the fifth organic solvent is selected from 2MeTHF, THF, and DCM.

414. The method of Embodiment 413, wherein the fifth organic solvent is THF.

415. The method of any one of Embodiments 412-414, wherein the third base is selected from LiO/Bu, NaOrBu, KO/Bu, LiO/Am, NaO/Am, and KO/Am.

416. The method of Embodiment 415, wherein the third base is KO/Bu.

417. The method of any one of Embodiments 410-416, wherein the method further comprises reacting A-(4-fluorophenyl)-6-((tctrahydro-2/7-pyran-4-yl)ethynyl)-l Zf-indazol-5-amine with a second acid to fonn 5-(4-fluorophenyl)-6-(tetrahydro-2//-pyran-4-yl)-l,5-dihydropyrrolo[2,3tjindazole.

418. The method of Embodiment 417, wherein reacting jV-(4-fluorophenyl)-6-((tetrahydro-

2H-pyran-4-yl)ethynyI)-lH-indazol-5-amine with a second acid to fonn 5-(4-fluorophenyI)-6(tetrahydro-277-pyran-4-yl)-l,5-dihydropyrrolo[2,3-f]indazole takes place at about 55-65 °C for no less than 3 hours.

419. The method of Embodiment 418, wherein reacting A-(4-fluoiOphenyl)-6-((tetrahydro2Z/-pyran-4-y])ethynyl)-177-indazol-5-amine with a second acid to fonn 5-(4-fluorophenyl)-6(tetrahydro-2Z7-pyran-4-yl)-l,5-dihydropyrrolo[2,3-f]indazole takes place at about 60 °C.

420. The method of any one of Embodiments 417-419, wherein the second acid is an organic acid, a strong acid, or a Lewis acid.

421. The method of Embodiment 420, wherein the second acid is acetic acid or NaHSO3.

262

422. The method of any one of Embodiments 417-421, wherein the method further comprises reacting 5-bromo-6-((tetrahydro-2Z-Z-pyran-4-yl)ethynyl)-l/Z-indazole with 4-fluoroaniline to fonn V-(4-fluorophenyI)-6-((tetrahydro-2H-pjTan-4-yl)ethynyl)-lÆ-indazol-5-amine.

423. The method of Embodiment 422, wherein reacting 5-bromo-6-((tetrahydro-2Æ-pyran-4yl)ethynyl)-l//-indazole with 4-fluoroaniline to form A^f-(4-fluorophenyl)-6-((tetrahydro-2Hpyran-4-yl)ethynyl)-IZZ-indazol-5-amine takes place at about 60-70 °C.

424. The method of Embodiment 423, wherein reacting 5-bromo-6-((tetrahydro-2/f-pyran-4yl)ethynyl)-lZZ-indazo!e with 4-fluoroaniline to form A-(4-fluorophenyl)-6-((tetrahydro-2Hpyran-4-yl)ethynyl)-1H-indazol-5-amine takes place at about 65 °C.

425. The method of any one of Embodiments 422-424, wherein reacting 5-bromo-6((tetrahydro-2//-pyran-4-yl)ethynyl)-lÆ-îndazole with 4-fluoroaniline to fonn Æ-(4fluorophenyl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-lZ/-indazol-5-amine takes place in the presence of a second catalyst, a sixth organic solvent, and a fourth base.

426. The method of Embodiment 425, wherein the second catalyst is selected from PdtBuXPhos Gl -4; (PdOAc)₂, Pd(cinnamyl)Cl₂ with ligands, BrettPhos, SPHos, XPhos, XantPhos, Pd(dppf)Cl₂*CH₂Cl₂, JosiPhos, and cataCXium® A.

427. The method of Embodiment 426, wherein the second catalyst is PdtBuXPhos.

428. The method of any one of Embodiments 425-427, wherein the sixth organic solvent is selected from EtOH, MeOH, l-butanol, tert-butanol, isopropyl alcohol (IPA), tAmOH, THF, 2MeTHF, CPMe, Toluene, DMF, ACN, DMA, and diglyme.

429. The method of Embodiment 428, wherein the sixth organic solvent îs EtOH.

430. The method of any one of Embodiments 425-429, wherein the fourth base is selected from NaOH, K3PO4, K₂CO3,NaOtBu, KOtBu, and NaOEt.

431. The method of Embodiment 430, wherein the fourth base is NaOtBu.

432. The method of any one of Embodiments 422-431, wherein the method further comprises reacting 5-bromo-6-iodo-177-indazole with trimethyI((tetraliydro-2ZZ-pyran-4-yl)ethnyl)silane to form 5-bromo-6-((tetrahydro-2EZ-pyran-4-yl)ethynyl)-lZ/-indazole.

263

433. The method of Embodiment 432, wherein reacting 5-bromo-6-îodo-l /f-indazole with trimethyl((tetrahydro-2Æ-pyran-4-yl)ethnyl)silane to form 5-bromo-6~((tetrahydro-2//-pyran-4yl)ethynyl)-l/7-indazoie takes place at about 70-80 °C.

434. The method of Embodiment 433, wherein reacting 5-bromo-6-iodo-lH-indazole with trimethyl((tetrahydro-2H-pyran-4-yl)ethnyl)siIane to form 5-bromo-6-((tetrahydro-2H-pyran-4yl)ethynyl)-l/f-indazole takes place at about 75 °C.

435. The method of any one of Embodiments 432-434, wherein reacting 5-bromo-6-iodo-lZ7indazole with trimethyl((tetrahydro-2J7-pyran-4-yi)ethnyl)silane to form 5-bromo-6-((tetrahydro2H-pyran-4-yl)ethynyl)-l//-indazole takes place in the presence of a seventh organic solvent, a fifth base, and a third catalyst.

436. The method of Embodiment 435, wherein the seventh organic solvent îs selected from DMF, EtOH, MeOH, 1-butanol, tert-butanol, isopropyl alcohol (IPA), tAmOH, aTHF/alcohol mixture, and a 2-MeTHF alcohol mixture.

437. The method of Embodiment 436, wherein the seventh organic solvent is EtOH.

438. The method of any one of Embodiments 435-437, wherein the fifth base is selected from

NaOH, KOH, K₂CO₃, Na₂CO₃, Cs₂CO₃ NaOtBu, ,KOtBu, and DBU (1,8Diazabicyclo(5.4.0)undec-7-ene).

439. The method of Embodiment 438, wherein the fifth base îs KOH.

440. The method of any one of Embodiment 435-439, wherein third catalyst is selected from Pd(PPh₃)4, Cul, CuI/PPh₃, and water.

441. The method of Embodiment 70, wherein the third catalyst is Pd(PPh₃)₄.

442. A compound selected from:

5-bromo-6-((tetrahydro-2Æ-pyran-4-yl)ethynyl)- 177-indazole (C2)

264

A^4-fluorophenyl)-6-((Îetrahydeo-2/7^}aui>4-yl)ethynyl-lH-indazole-5-amine (C12)

5-(4-fluorophenyl)-6-(tetrahydro-2H-pyrarL-4-yl)-l,5-dihydropyrrolo[2,3-f]indazole (C13)

l-(5-(4-fluorophenylj-6-(tetrahydiΌ-2H-pyran-4-yl)pyrro!o[2_:3-f]lndazol-l(5l·ΓLyl)-2_Ί2dimethylpropan-l-one (€14)

l-(5-(4-fluorophenyl)-7-iodo-6-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,3-f]indazol-l(5H)10 yl)-2,2-dimethylpropan-l-one (S4)

methyl 4-(5-(4-fluorophenyI)-l-pivaloyl-6-(tetrahydro-2H-pyran-4-yl)-l ,5dihydropynOlo[2,3-f]indazol-7-yl)benzoate (C58)

265

443. Neat amorphous Compound 33.

444. The neat amorphous Compound 33 according to Embodiment 443, characterized as having a ¹³C solid state nuclear magnetic résonance (^l3C ssNMR) spectrum with peaks at 16I.6 ± 0.2 ppm, 130.7 ± 0.2 ppm, 121.4 ± 0.2 ppm, and 115.7 ± 0.2 ppm.

445. The neat amorphous Compound 33 according to Embodiment 443, characterized as having a ^l3C ssNMR spectrum with (a) peaks at 161.6 ± 0.2 ppm, 130.7 ± 0.2 ppm, 121.4 ± 0.2 ppm, and 115.7 ±0.2 ppm; and (b) one, two, three, four, five, six, seven, or more peaks selected from 172.5 ± 0.2 ppm, 170.1 ± 0.2 ppm, 167.0 ± 0.2 ppm, 163.7 ± 0.2 ppm, 144.5 ± 0.2 ppm, 140.8 ± 0.2 ppm, 137.4 ± 0.2 ppm, 97.6 ± 0.2 ppm, 67.9 ± 0.2 ppm, 35.3 ± 0.2 ppm, and 31.5 ± 0.2 ppm.

446. The neat amorphous Compound 33 according to Embodiment 443, characterized as having a ^I3C ssNMR spectrum with (a) peaks at 161.6 ± 0.2 ppm, 130.7 ± 0.2 ppm, 121.4 ± 0.2 ppm, and 115.7 ± 0.2 ppm; and (b) two or more peaks selected from 172.5 ± 0.2 ppm, 170.1 ± 0.2 ppm, 167.0 ± 0.2 ppm, 163.7 ± 0.2 ppm, 144.5 ± 0.2 ppm, 140.8 ± 0.2 ppm, 137.4 ± 0.2 ppm, 97.6 ± 0.2 ppm, 67.9 ± 0.2 ppm, 35.3 ± 0.2 ppm, and 31.5 ± 0.2 ppm.

447. The neat amorphous Compound 33 according to Embodiment 443, characterized as having a ^I3C ssNMR spectrum with (a) peaks at 161.6 ± 0.2 ppm, 130.7 ± 0.2 ppm, 121.4 ± 0.2 ppm, and 115.7 ± 0.2 ppm; and (b) three or more peaks selected from 172.5 ± 0.2 ppm, 170.1 ± 0.2 ppm, 167.0 ± 0.2 ppm, 163.7 ± 0.2 ppm, 144.5 ± 0.2 ppm, 140.8 ± 0.2 ppm, 137.4 ± 0.2 ppm, 97.6 ± 0.2 ppm, 67.9 ± 0.2 ppm, 35.3 ± 0.2 ppm, and 31.5 ± 0.2 ppm.

266

44S. The neat amorphous Compound 33 according to Embodiment 443, characterized as having a ^I3C ssNMR spectrum with (a) peaks at 16I.6 ± 0.2 ppm, 130.7 ± 0.2 ppm. 12E4 ± 0.2 ppm, and 115.7 ± 0.2 ppm; and (b) four, five, six, seven or more peaks selected from 172.5 ± 0.2 ppm, 170.1 ± 0.2 ppm, 167,0 ± 0.2 ppm, 163.7 ± 0.2 ppm, 144.5 ± 0.2 ppm, 140.8 ± 0.2 ppm, 137.4 ± 0.2 ppm, 97.6 ± 0.2 ppm, 67.9 ± 0.2 ppm, 35.3 ± 0.2 ppm, and 31,5 ± 0.2 ppm.

449. The neat amorphous Compound 33 according to Embodiment 443, characterized as having a ¹³C ssNMR spectrum substantially similar to FIG. 38C.

450. The neat amorphous Compound 33 according to any one of Embodiments 443-449, characterized as having a ¹⁹F solid state nuclear magnetic résonance (^l9F ssNMR) spectrum with a peak at -112.8 ± 0.2 ppm.

451. The neat amorphous Compound 33 according to anyone of Embodiments 443-449, characterized as having ¹⁹F ssNMR spectrum substantially similar to FIG. 38D.

452. A spray dried neat amorphous Compound 33 according to any one of Embodiments 443451.

453. A pharmaceutical composition comprising spray-dried neat amorphous Compound 33 according to any one of Embodiments 443-451.

454. A solid dispersion comprising substantially amorphous Compound 33 and a polymer.

455. The solid dispersion comprising substantially amorphous Compound 33 according to Embodiment 454, wherein the polymer is selected from polyvinylpyrrolidone/vmyl acetate (PVPVA), hydroxypropylmethylcellulose (HPMC), and hydroxypropylmethylcellulose acetate succinate (HPMCAS).

456. The solid dispersion comprising substantially amorphous Compound 33 according to Embodiment 454 or Embodiment 455, wherein substantially amorphous Compound 33 is present in an amount from 30-50%.

267

457. The solid dispersion comprising substantially amorphous Compound 33 according to Embodiment 454 or Embodiment 455, wherein substantially amorphous Compound 33 is présent in an amount from 50-80%.

458. The solid dispersion comprising substantially amorphous Compound 33 according to any one of Embodiments 454-457 prepared as a spray-dried dispersion.

459. A solid dispersion comprising 50% amorphous Compound 33 and HPMCAS, characterized as having a ^I3C ssNMR spectrum with at least 5, at least six, at least 8, at least 10, or at least 12 peaks selected from 173.1 ± 0.2 ppm, 170.0 ± 0,2 ppm, 167.2 ± 0.2 ppm, 163.9 ± 0.2 ppm, 161.5 ± 0.2 ppm, 144.4 ± 0.2 ppm, 141.2 ± 0.2 ppm, 137.8 ± 0.2 ppm, 130.9 ± 0.2 ppm, 121.7 ± 0.2 ppm, 116.5 ± 0.2 ppm, 103.0 ± 0.2 ppm, 98.4+ 0.2 ppm, 83.5 ± 0.2 ppm, 74.1 ± 0.2 ppm, 68.5 ± 0.2 ppm, 60.5 ± 0.2 ppm, 35.8 ± 0.2 ppm, 30,7 ± 0.2 ppm, 20.6 ± 0.2 ppm, and 16.5 ±0.2 ppm.

460. The solid dispersion comprising 50% amorphous Compound 33 and HPMCAS, according to Embodiment 459, characterized as having a ¹³C ssNMR spectrum substantially similar to FIG. 30D.

461. The solid dispersion comprising 50% amorphous Compound 33 and HPMCAS, according to Embodiment 459 or Embodiment 460, characterized as having a ¹⁹F ssNMR spectrum with a peak at -112.6 ± 0.2 ppm.

462. The solid dispersion comprising 50% amorphous Compound 33 and HPMCAS, according to any one of Embodiments 459-461, characterized as having ^l9F ssNMR spectrum substantially similar to FIG. 30E.

463. A solid dispersion comprising 80% amorphous Compound 33 and HPMCAS, characterized as having a ^l3C ssNMR spectrum with at least 5, at least six, at least 8, at least 10, or at least 12 peaks selected from 173.0 ± 0.2 ppm, 169.6 ± 0.2 ppm, 163,8 ± 0.2 ppm, 161.2 ± 0.2 ppm, 144.1 ± 0.2 ppm, 140.9 ± 0.2 ppm, 137.6 ± 0.2 ppm, 130.9 ± 0.2 ppm, 121.6 ± 0.2 ppm, 116.3 ± 0.2 ppm, 103.2 ± 0.2 ppm, 98.1 ± 0.2 ppm, 82.9 ± 0.2 ppm, 74.6 ± 0.2 ppm, 68.2 ± 0.2 ppm, 60.5 ± 0.2 ppm, 35.6 ± 0.2 ppm, 31.5 ± 0.2 ppm, and 20.1 ± 0.2 ppm.

268

464. The solid dispersion comprising 80% amorphous Compound 33 and HPMCAS, according to Embodiment 463, characterized as having a ^l3C ssNMR spectrum substantially similar to FIG. 34C.

465. The solid dispersion comprising 80% amorphous Compound 33 and HPMCAS, according to Embodiment 463 or Embodiment 464, characterized as having a ^l9F ssNMR spectrum with a peak at -112.6 ± 0.2 ppm.

466. The solid dispersion comprising 50% amorphous Compound 33 and HPMCAS, according to anyone of Embodiments 463-465, characterized as having ^l9F ssNMR spectrum substantially similar to FIG. 34D.

EXAMPLES

In order that the disclosure described herein may be more fully understood, the following examples are set forth. It should be understood that these ex amples are for illustrative purposes only and are not to be construed as limiting this disclosure in any manner.

EXAMPLE 1, Synthesis of Compounds

Ail the spécifie and generic compounds, and the intermediates disclosed for making those compounds, are considered to be part of the invention disclosed herein.

269

Préparation SI

5-(3,4-difluorophenyl)-7-iodo-l-(phenylsulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-l, 5dihydropyrrolof2,3-f]indazole (SI)

Step 1. Synthesis of5-bromo-6-(2-tetrahydropyran-4-ylethynyl)-ÎH-indazole (C2)

To a solution of 5-bromo-6-iodo-lH-indazole Cl (100 g, 294,2 mmol) in 1,4-dioxane (500 mL) was added Et₃N (500 mL, 3.6 mol), copper iodide (3.4 g, 17.9 mmol), CsF (89.4 g, 588.5 mmol), H₂O (10.6 mL, 588.4 mmol), and Pd(PPh₃)₂Cl₂ (6.2 g, 8.8 mmol). Trimethyl((tetrahydro-2H-pyran-4-yl)ethynyl)silane (67 g, 367.5 mmol) was added, and the 10 reaction mixture was purged with nitrogen for 15 min, then heated to 80 °C ovemight. Upon cooling, Et₃N and 1,4-dioxane were removed by concentration în vacuo. Water (200 mL) and brine (200 mL) were added and the mixture was extracted with EtOAc (1.4 L). The combined organic layers were dried and concentration in vacuo. Ethyl acetate ( 120 mL) was added, and the mixture stirred for 1 h. The resulting solid which formed was filtered, and washed with EtOAc (x 15 2) to afford the desired product as a solid (43 g). The fîltrate was concentrated and purified by silica gel chromatography (Column: 800 g Silica Gel. Eluent: 25 % CH₂C1₂ in heptane, followed by a gradient of 0-90 % CH₂C1₂ in heptane) to afford additional product as a brown solid (29 g). The product batches were combined to afford the product as a brown solid (72 g, 80 %). 'H 270

NMR(300MHz, Chloroform-d) δ 10.43 (s, IH), 8.00 (dd, J = 3.0, 0.9 Hz, 2H), 7.62 (t, J = 0.8 Hz, IH), 4.02 (ddd, J = H.6, 6.5, 3.5 Hz, 2H), 3.62 (ddd, J = 11.3, 7.7, 3.2 Hz, 2H), 2.98 (tt, J = 8.0, 4.2 Hz, IH), 2.02 - 1.89 (m, 2H), 1.82 (dtd, J = 13.4, 7.7, 3.5 Hz, 2H). LCMS m/z 306.8 [M+H]⁺.

Step 2. Synthesis ofN-(3,4~difluorophenyl)-6-(2-tetrahydropyran-4-ylethynyl)-lH-indazol-5amine (C3)

5-bromo-6-(2-tetrahydropyran-4-ylethynyl)-lH-indazole C2 (51.9 g, 170.1 mmol), 3,4difluoroanilîne (25.3 mL, 255.1 mmol), and NaOtBu (49 g, 509.9 mmol) were added to a Parr bottle. THF (625 mL) was added, and the mixture was then degassed with nitrogen for a -10 min. BrettPhos Pd G1 (6.8 g, 8.5 mmol) was added, and the mixture degassed further. The reaction was allowed to stîr at 70 °C for 120 min. The mixture was concentrated in vacuo, then diluted with CH2CI2 (1 L). The organic layer was washed with 50% saturated sodium bicarbonate (-700 mL). The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. Two additional 50 g batches of C2 were processed as described. The combined products were purified by silica gel chromatography (Column: 3 kg Silica. Gradient: 0-100 % EtOAc in heptane) to afford the product (155.2 g, 83 %). ’H NMR (300 MHz, DMSOdf) δ 13.06 (s, IH), 8.00 (t, J = 1.2 Hz, IH), 7.72 (s, IH), 7.64 - 7.58 (m, IH), 7.55 (s, IH), 7.26 7.08 (m, IH), 6.69 (ddd, J = 13.4, 7.0, 2.7 Hz, IH), 6.62 - 6.52 (m, IH), 3.72 - 3.61 (m, 2H), 3.43 - 3.35 (m, 2H), 2.88 - 2.76 (m, IH), 1.76 - 1.64 (m, 2H), 1.50 - 1.34 (m, 2H). LCMS m/z 354.2

[M+H]⁺.

Step 3. Synthesis of 5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-rH-pyrrolo[2,3-f]indazole (C4)

N-(3,4-difluorophenyl)-6-(2-tetrahydropyran-4-ylethynyl)-1 H-indazol-5-amine C3 (155.2 g, 439.2 mmol) was dissolved in DMSO (650 mL) and placed in a 2 L Parr bottle. The reaction was sealed and heated at 150-160 °C for 120 min, and then cooled to room température.

% saturated sodium bicarbonate (6.5 L) was added to the reaction mixture. Upon stirring for 1 h, the mixture was filtered, the filter cake washed with additional water, and dried under vacuum at 50 °C for 2 days to afford the product (146 g, 89 %). ^lH NMR (300 MHz, DMSO-c/₆) δ 12.63 (s, IH), 7.98 (s, IH), 7.81 - 7.63 (m, 2H), 7.57 (t, J = 1.1 Hz, IH), 7.44 - 7.33 (m, IH), 7.25 (t, J =0.9 Hz, IH), 6.52 (d, J = 0.8 Hz, IH), 3.85 (dt, J = 11.5, 3.2 Hz, 2H), 3.28 (td, J = 11.3, 3.5 Hz,

2H), 2.88 (tt, J = 10.0, 4.9 Hz, IH), 1.78 - 1.58 (m, 4H). LCMS m/z 354.2 [M+H]⁺.

Step 4. Synthesis of l-(benzenesulfonylf5f3,4-difluorophenyl)-6-tetrahydropyran-4-ylpyrrolo[2,3-fj indazole (C5)

To a solution of 5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3-f]indazole

C4 (15 g, 40.8 mmol) in THF (175 mL) was added KOtBu (5.9 g, 52.6 mmol) and the mixture 271 was stirred at room température for 10 min. The reaction w'as cooled to 0 °C in an ice bath, then benzenesulfonyl chloride (6.7 mL, 52.5 mmol) was added dropwise over 2 h. The mixture was allowed to stir at 0 °C for an additional 2 h. Aqueous NH₄Cl_(sat.), water and CH₂CL was added. The organic phase was separated on a phase separator and purified by silica gel chromatography 5 (Eluent: Ethyl acetate/CH₂Cl₂) to afford the product (15.2 g, 73%). *H NMR (400 MHz,

DMSO-îZ₆) δ 8.47 (s, IH), 8.24 (s, IH), 7.84 (t, J = 8.7 Hz, 3H), 7.68 (dt, J - 26.0, 8.4 Hz, 2H), 7.53 (t, J = 7.7 Hz, 2H), 7.47 - 7.28 (m, 2H), 6.75 (s, IH), 3.86 (d, J = 11.4 Hz, 2H), 3.33 - 3.16 (m, -2H), 2.89 (d, J = 5.8 Hz, IH), 1.71 (t, J = 5.6 Hz, 4H). LCMS m/z 494.3 [M+H]⁺.

Step 5. Synthesis of l-(benzenesulfonyl)-5-(3,4-difluorophenyl)-7-iodo-6-tetrahydropyran-4-yl10 pyrrolo[2,3-f]indazole (SI) l-iodopyrrolidine-2,5-dione (1.1 g, 4.4 mmol) was added to a solution of 1(benzenesulfonyl)-5-(3,4-difluorophenyl)-6-tetrahydropyran-4'yl-pynOlo[2,3-fJindazole C5 (2.2 g, 4.5 mmol) in CH^CL (25 mL) at room température over l h. The mixture was allowed to stir overnight and then purified by silica gel chromatography (Eluent: Ethyl acetate / CH2CL) to 15 afford the product (2.33 g, 84 %). ‘H NMR (400 MHz, DMSO-c/ô) δ 8.51 (s, IH), 8.05 (s, IH), 7.82 (d, J = 7.9 Hz, 3H), 7.80 - 7.62 (m, 2H), 7.56 (t, J = 7.7 Hz, 2H), 7.43 (d, J = 8.9 Hz, IH), 7.33 (s, IH), 5.76 (s, 3H), 3.97 - 3.73 (m, 2H), 3.32 - 3.17 (m, IH), 2.92 (t, J = 12.3 Hz, IH), 2.30 (dd, J = 16.3, 10.0 Hz, 2H), 1.66 (d, J = 13.0 Hz, 2H). LCMS m/z 620.2 [M+l]⁺.

272

Préparation S2 l-(5-( 3fluorophenyl)-7-iodo-6-methylpyrrolo[2,3-f]indazol-l(5H)-yl)-2,2-dimethylpropan-l-one (S2)

Step I. Synthesis of 5-chloro-6-prop-l-ynyl-lH-indazole (C7)

6-bromo-5-chloro-lH-indazole C6 (1.5 g, 6.5 mmol) and Pd(dpppf)₂Cl₂ (550 mg, 0.67 mmol) were added to a Parr bottle. 1,4-dioxane (50 mL) was added and the vessel flushed with nitrogen. tributyl(prop-l-ynyl)stannane (3 mL, 9.9 mmol) was added, and the reaction heated to 115 °C ovemight. The reaction mixture was adsorbed onto Celite® and purified by silica gel chromatography (Gradient: 0-100 % ethyl acetate in heptane) to afford the product (0.77 g, 56 %). LCMS m/z 191.1 [M+H] ^h.

Step 2. Synthesis o/'5-(3-fluorophenyl)-6-methyl-lH-pyrrolo[2,3-f]indazole (C8)

5-chloro-6-prop-l-ynyl-lH-indazole C7 (770 mg, 3.7 mmol), 3-fluoroaniline (600 pL, 6.2 mmol), sodium t-butoxide (1.1 g, 11.0 mmol), and BrettPhos Pd G3 (160 mg, 0.18 mmol) were added to a vial. m-Xylene (13 mL) was added and the mixture purged with nitrogen. The reaction was allowed to stir at 115 °C ovemight. The mixture was then concentrated in vacuo, diluted with ethyl acetate (20 mL) and washed with 50 % saturated sodium bicarbonate (20 mL). The organic layer was dried sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography (Gradient: 0-100 % ethyl acetate in heptane) afforded the product (179 mg, 18 %). *H NMR(300MHz, DMSO-^) δ 12.62 (s, IH), 7.99 (t, J = 1.3 Hz, IH), 7.72 - 7.61 (m, IH), 7.55 - 7.49 (m, IH), 7.45 (dt, J = 10.0, 2.3 Hz, IH), 7.40 - 7.30 (m, 3H), 6.48 (t, J = 1.0 Hz, IH), 2.33 (d, J = 1.0 Hz, 3H). LCMS m/z 266.2 [M+H]⁺.

273

Step 3. Synthesis of 1 -[5-(3-fluorophenyl)-6-methyl-pyrrolo[2,3-]]indazol-l-yl]-2,2-dimethvlpropan-I-one (C9)

To a solution of 5-(3-fluorophenyl)-6-methyl-lH-pyrrolo[2,3-fjindazole C8 (177 mg, 0.65 mmol) in THF (3.5 mL) at I °C (ice-water bath) was added KOtBu (881 pL of 1 M, 0.9 mmol). After -10 min, 2,2-dimethylpropanoyl chloride (108 pL, 0.9 mmol) was added and the mixture allowed to stir for 30 min. An additional 25 pl of 2,2-dimethylpropanoyl chloride was added and the mixture stirred for an additional -30 min in an ice bath. The reaction was quenched with water (3 mL), stirred for 5 min and concentrated to in vacuo. The residue was partitioned between CH₂C1₂ (10 mL) and water (10 mL). The organic layer was isolated, washed with water, passed through a phase separator and concentrated in vacuo. Silica gel chromatography (Gradient: 0-50% ethyl acetate in heptane) afforded the product (151 mg, 64 %). ‘H NMR(400MHz, DMSO-^) Ô 8.48 (s, IH), 8.40 (d, J = 0.8 Hz, IH), 7.73 - 7.64 (m, IH), 7.54 - 7.47 (m, 2H), 7.45 - 7.36 (m, 2H), 6.68 - 6.63 (m, IH), 2.37 (d, J = 1.0 Hz, 3H), 1.52 (s, 9H). LCMS m/z 350.3 [M+H] 7

Step 4. Synthesis of l-[5-(3-fliiorophenyl)-7-iodo~6-methyl-pyrrolo[2,3-f]indazol-l-yl]-2,2dimethyl-propan-1 -one (S2) l-iodopyrrolidine-2,5-dione (97 mg, 0.41 mmol) was added portion-wise to a solution of l-[5-(3-fluorophenyl)-6-methyl-pynOlo[2,3-f]indazoI-I-yl]-2,2-dimethyl-propan-l-one C9 (148 mg, 0.41 mmol) in CH₂C1₂ (2 mL) at room température. The mixture was stirred for 1 h, and diluted with CH₂C1₂ (5 mL). The mixture was washed with 50 % saturated sodium bicarbonate (5 mL). The organic layer was separated on a phase separator and then concentrated in vacuo to afford the product (195 mg, 97 %). ^]H NMR(400MHz, DMSO-^₆) 5 8.46 (d, J = 0.S Hz, IH), 8.34 - 8.30 (m, IH), 7.70 (td, J = 8.2, 6.5 Hz, IH), 7.58 - 7.53 (m, 2H), 7.48 - 7.40 (m, 2H), 2.42 (s, 3H), 1.53 (s, 9H). LCMS m/z 476.3 [M+H]⁺.

274

Préparation S3 i-(5-(3 -fluorophenyl)-7-iodo-6-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,3-f]indazol-1 (5 H) -yl)-2,2dimethylpropan-1 -one (S3)

Step 1. Synthesis of 5-(3-fluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3-f]indazole (CIO) 5-bromo-6-(2-tetrahydropyran-4-ylethynyl)-IH-indazole C2 (3 g, 9.8 mmol), 3fluoroaniline (1.5 mL, 15.6 mmol), and NaOtBu (2.8 g, 29.1 mmol) were added to a Parr bottle. THF (65 mL) w^ras added, and the mixture purged with nitrogen for -10 min. BrettPhos (388 mg, 0.49 mmol) was added, and the mixture further purged with nitrogen. The reaction was heated at 50 °C ovemight, then diluted with EtOAc (150 mL). The mixture was then washed with 50 % saturaied sodium bicarbonate (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography (Gradient: 0-100 % ethyl acetate in heptane) afforded the product (3.06 g, 91 %). *H NMR (300 MHz, DMSO-r/₀) δ 13.05 (s, IH), 8.04 - 7.92 (m, IH), 7.78 (s, IH), 7.60 (d, J = 6.1 Hz, 2H), 7.19 - 7.05 (m, IH), 6.60 (ddd, J = 8.2, 2.0, 0.9 Hz, IH), 6.52 - 6.36 (m, 2H), 3.72 - 3.59 (m, 2H), 3.42 - 3.32 (m, 2H), 2.87-2.75 (m, IH), 1.75 - L61 (m, 2H), 1.49 - 1.34 (m, 2H).

Step 2. Synthesis of l-[5-(3-fluorophenyl)-6y-tetrahydropyran-4-yl-pyrrolo[2,3-f]îndazol-I-yl]2,2-dimethyl-propan-l-one (Cil)

To a suspension of 5-(3-fluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3-f]indazole CIO (1.65 g, 4.9 mmol) in THF (40 mL) at I °C (ice-water bath) was added KOtBu (6.5 mL of 1 M, 6.5 mmol). After ~10 min, 2,2-dimethylpropanoyl chloride (806 pL, 6.6 mmol) was added,

275 and the reaction was allowed to stir for 30 min. An additional 80 pL of 2,2-dimethylpropanoyl chloride was added, and the mixture allowed to stir for an additional ~30 min. The reaction mixture was quenched with water (5 mL), stirred for 5 min, and then concentrated to dryness under reduced pressure. The mixture was partitioned between CH2CI2 (l 00 mL) and water (50 mL). The organic layer was washed with water, passed through a phase separator and concentrated in vacuo. Silica gel chromatography (Gradient: 0-50 % ethyl acetate in heptane) afforded the product (L75 g, 84 %). ’H NMR (400 MHz, DMSO-î/₆) 5 8.40 (d, J = 0.8 Hz, IH), 8.37 - 8.33 (m, IH), 7.97 (s, IH), 7.70 (s, IH), 7.27 - 7.19 (m, IH), 6.82 (ddd, J = 8.2, 2.2, 0.8 Hz, IH), 6.74 (dt, J = 11.8, 2.3 Hz, IH), 6.64 - 6.57 (m, IH), 3.76 - 3.65 (m, 2H), 3.45 - 3.36 (m, 2H), 2.95 - 2.84 (m, 1 H), 1.81 - 1.71 (m, 2H), 1.54 - 1.44 (m, 1 IH). LCMS m/z 420.3 [M+H]⁺. Step 3. Synthesis of I-[5-(3-fluorophenyl)-7-iodo-6-tetrahydropyran-4-yl-pyrrolo[2,3-f]indazoll-yl]-2,2-dimethyl-propan-l-one (S3) l-iodopyrrolidine-2,5-dione (112 mg, 0.5 mmol) was added portion-wise to a solution of l-[5-(3-fluorophenyl)-6-tetrahydropyran-4-yl-pyrrolo[2,3-f]indazol-l-yl]-2,2-dimethyl-propan1-one Cil (202 mg, 0,5 mmol) in CH2CI2 (3 mL), and the reaction allowed to stir at room température for 1 h. The mixture was diluted with CH2CI2 (5 mL), washed with 50 % saturated sodium bicarbonate (5 mL). The organic layer was passed through a phase separator, and concentrated to dryness under reduced pressure. The resulting solid was dried under vacuum for 2 h to afford the product (237 mg, 87 %). ‘H NMR(300MHz, DMSO-d₆) δ 8.44 (d, J = 0.8 Hz, IH), 8.39 (t, J = 0,9 Hz, IH), 7.77 - 7.68 (m, IH), 7.58 - 7.51 (m, 2H), 7.42 - 7.36 (m, IH), 7.34 (d, J = 1.0 Hz, IH), 3.96 - 3.88 (m, 2H), 3.23 (t, J = 12.1 Hz, 2H), 2.96 (t, J = 12.6 Hz, IH), 2.38 2.26 (m, 2H), 1.67 (d, J = 12.7 Hz, 2H), 1.52 (s, 9H). LCMS m/z 546.4 [M+Hf.

276

Préparation S4 l-(5-(4-fluorophenyl)- 7-iodo-6-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,3-f] indazol-1 (5H)-yl)-2,2dimethylpropan-l-one (S4)

Steps î & 2. Synthesis o/'5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3-f]indazole (CI3)

A mixture of 5-bromo-6-(2-tetrahydropyran-4-ylethynyl)-lH-indazoIe C2 (160 g, 524.3 mmol), 4-fluoroaniline (75 mL, 791.7 mmol), NaOtBu (90 g, 936.5 mmol) în tBuOH (2.1 L) at 40 °C was purged with nitrogen for 10 min. tBuXPhos Pd GI (10.8 g, 15.7 mmol) was added, 10 and the mixture purged with nitrogen for an additional 10 min. The mixture was heated to 80 °C for 1 h, and then concentrated in vacuo. CH2CI2 (1.5 L), saturated NH4CI (1 L), and HCI (62 mL of 6 M, 372.0 mmol) were added. The organic layer was dried with Na₂SO4, concentrated in vacuo, and re-dissolved in CH2CI2 (160 mL). The mixture was fïltered to remove the white inorganic solid. The filtrate was then purified by silica chromatography (Column: 3 kg Silica gel.

Gradient: 0-90% EtOAc in heptane) to afford the product contaminated with 4-fluoroaniline. The mixture was dissolved in EtOAc (1.5 L), a washed with IN HCl (2 x 250 mL), then brine.

277

The organic layer was dried, and concentrated in vacuo to afford the product as a sticky solid, which was used without further purification (160 g, 91 %). LCMS m/z 336.1 [M+H]⁺.

A solution of N-(4-fluorophenyl)-6-(2-tetrahydropyran-4-ylethynyl)-lH-indazol-5-amine C12 in DMSO (550 mL) was heated to 160 °C for 1.5 h. The mixture was cooled, and sat. Na^COî (500 mL) and water (1.5 L) were added. The mixture was allowed to stir overnight. The resulting grey solid suspension was filtered, and the filter cake was washed with water (x 3), then heptane (x 3). The filter cake was suspended in TBME (300 mL) and stirred. Solvent was then removed by concentration in vacuo. The resulting solid was dried under vacuum overnight to afford the product (134 g, 76 %). *H NMR(300MHz, DMSO-î/₆) δ 12.62 (s, IH), 7.97 (s, IH), 7.66 - 7.35 (m, 5H), 7.17 (s, IH), 6.51 (s, IH), 3.93 - 3.75 (m, 2H), 3.24 (td, J = 11.3, 5.2 Hz, 2H), 2.82 (dt, J = 10.4, 6.3 Hz, IH), 1.70 (dt, J = 10.1, 4.8 Hz, 4H). LCMS m/z 336.1 [M+H]⁺.

Step 3. Synthesis of I-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-pyrrolo[2,3-f]indazol-l-yl]2,2-dimethyl-propan-I-one (Cl 4)

To a solution of 5-(4-fiuorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3-f]indazole C13 (10 g, 29.S mmol) in THF (320 mL) at 0 °C was added KO/Bu (7.4 g, 65.7 mmol) and the mixture allowed to stir for 5 min. 2,2-dimethyIpiOpanoyl chloride (14.5 mL, 117.9 mmol) was added and the mixture allowed to stir for 1 h. Water (200 mL) and CH₂Cb (250 mL) were added and the mixture extracted with additional dichloromethane (2 x 50 mL). The organic layer was dried over Na₂SO4 and concentrated in vacuo. Purification b y silica gel chromatography (Gradient: 0-5 % EtOAc in Heptane) afforded the product as light yellow solid. 1-(5-(4fluorophenyl)-6-tetrahydropyran-4-yl-pyrrolo[2,3-f]indazol-l-yl]-2,2-dimethyl-propan-l-one (10.7 g, 83 %). ‘H NMR (400 MHz, Chloroform-d) δ 8.69 (s, IH), 8.07 (s, IH), 7.39 (dd, J = 8.4, 4.9 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H), 7.21 (s, IH), 6.59 (s, IH), 4.01 (dd, J = 12.0, 4.1 Hz, 2H), 3.37 (t, J = 11.7 Hz, 2H), 2.89 - 2.80 (m, IH), 1.89 (qd, J = 12.2, 4.1 Hz, 2H), 1.78 (d, J = 13.0 Hz, 2H), 1.61 (d, J = 1.3 Hz, 9H). LCMS m/z 420.3 [M+H]⁺.

Step 4. Synthesis of l-[5-(4-fluorophenyl)-7-iodo-6-tetrahydropyran-4-yl-pyrrolo[2,3-f]indazoll-yl]-2,2-dimethyl-propan-l-one (S4) l-iodopyrrolidine-2,5-dione (7.4 g, 31.2 mmol) was added portion-wise over 30 min to a solution of 1-(5-(4-tluorophenyl)-6-tetrahydropyran-4-yl-pyrrolo[2,3-f]Lndazol-l-yl]-2,2dimethyl-propan-1-one C14 (10.7 g, 25.4 mmol) in CH2CI2 (110 mL). The reaction was stirred at room température for 30 min. Purification by silica gel chromatography (Gradient: 0-5 % EtOAc in Dichloromethane) resulted in an orange solid, which was triturated with heptane. Water (250 mL) was then added, and the mixture stirred vigorously for 30 min. The solid was filtered, washed with excess water then dissolved in CH2CI2 (250 mL). The solution was washed with water (250 mL) and the organic phase dried (phase separator) and concentrated in vacuo to 278 afford the product as a light tan solid (11.7 g, 84 %). ^JH NMR (400MHz, Chloroform-d) δ 8.63 (s, JH), 8.0S (s, IH), 7.37 - 7.30 (m, 4H), 7.08 (s, IH), 4.04 (dd, J = 11.7, 4.2 Hz, 2H), 3.38 (t, J = 11.8 Hz, 2H), 3.07 (t, J = 12.6 Hz, IH), 2.43 (qd, J = 12.5, 4.3 Hz, 2H), 1.62 (s, 9H). LCMS m/z 546.33 [M+H]⁺.

Alternative Préparation ofl-[5-(4-fluorophenyl)-7-iodo-6-tetrahydropyran-4-yl-pyrrolo[2,3fjindazol-l-yl]-2,2-dimethyl-propan-1 -one (S4)

1. tBuXPhos Pd G1 NaOtBu

C2

2. AcOH

Step 1. Synthesis of 5-bromo-6-(2-tetrahydropyran-4-ylethynyl)-1 H-indazole (C2)

To reactor A under N₂ was charged 5-bromo-6-(2-tetrahydropyran-4-ylethynyl)-l H10 indazole Cl (12.0 kg), PdCl₂(PPh₃)₂, (0.26 kg), and Cul (0.35 kg). Reactor A was degassed (vacuum / nitrogen purges x 2). To reactor B was charged EtOH (52.1 kg) (to aid in the transfer of trimethyl((tetrahydro-2H-pyran-4-yl)ethynyl)silane), and degassed with (vacuum / nitrogen purges x 2). To reactor A was charged trimethyl((tetrahydro-2H-pyran-4-yl)ethynyl)silane (7.42 kg) and EtOH (4.7 kg). To reactor A was charged 45 wt % KOH (9.72 kg) and EtOH (4.6 kg) 15 (to aid in the transfer of the 45 wt % KOH). The agitator was started in Reactor A, the vessel was then degassed (vacuum / nitrogen purges x 4), and the contents of Reactor A were heated to 279 ± 5° C. The reaction was held at 76.5 to 77.0 °C for 2 h, and then cooled to 40.1 °C over 20 min. The contents of reactor A were concentrated to a volume of 24 L by vacuum distilled with the maximum température of 35.1 °C. The contents of reactor A were adjusted to 13.5 °C. To a drum was added water (73.9 kg) and concentrated HCl (4.1 kg). The HCl transfer line was 5 rinsed with water (4.7 kg) and charged to the drum. The contents ofthe drum were mixed (0.5

M HCl soin). The 0.5 M HCl solution (73.9 kg) was transferred to Reactor A over 21 min to cause précipitation of 5-bromo-6-(2-tetrahydropyran-4-ylethynyl)-lH-indazole C2 and a maximum température of 20.9 °C (spec. 20 ± 5 °C) during the addition. An aliquot ofthe slurry was taken and the pH was measured to be 2.0 with a calibrated pH probe. KOH (45 wt%, 0.3 10 kg) was charged to Reactor A to give a reaction température of 15.4 °C. An aliquot of the slurry was taken and the pH was measured to be 10.3 with a calibrated pH probe. HCl (0.5 Μ, 1.2 kg) was transferred over 2 min to reactor A with a maximum température of 13.8 °C. An aliquot of the slurry was taken and the pH was measured to be 6.03 with a calibrated pH probe. The contents of reactor A were adjusted to 22.1 °C and held for 1 h at 22.1 °C. The contents of 15 reactor A were filtered (filtration time 27 min) and washed with water (2 x 36 kg). The solids were dried on the filter for 50 min, then dried on trays at 50-55 °C for 16 h to afford the product C2.

Step 2. Synthesis of 5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3-f]indazole (Cl3) NaOtBu, 97 % (39.2 g, 407.4 mmol, 2.1 equiv.) was added to a reactor. Ethanol 20 (355.2 mL, 6 vols) was added (Note: exothermic reaction) and the mixture was purged with nitrogen. 5-bromo-6-[2-(oxan-4-yl)ethynyl]-lH-indazole C2 (59.2 g, 194 mmol, 1 equiv.) was added at 20 °C to the reactor. 4-fluoroaniline (23.71 g, 20.3 mL, 213.4 mmol, 1.1 equiv.) was then added and the mixture degassed (vacuum and nitrogen purge cycles x 3). t-BuXPhos Pd Gt (4.0 g, 5.82 mmol, 0.03 equiv.) at 20 °C was added and the mixture degassed again (vacuum and 25 nitrogen purge cycles x 3). The reactor was heated to 65 °C internai température for 2 h, then cooled to 60 °C. AcOH (55.3 g, 52.8 mL, 921.5 mmol, 4.75 equiv.) at 60 °C was added (Note exothermic reaction, solids precipitate during addition) and the réaction allowed to stir at 60-63 °C for 2 h. The mixture was then cooled to 25 °C. Dichloromethane (8 vol) was added to the mixture. 0.5 M NaOH (5 vol) was added and the phases were stirred vigorously for 20 minutes. 30 Additional 0.5 M NaOH was added to adjust the pH to pH 6-7. The phases were separated, and the aqueous phase was separated and extracted with dichlormethane (4 vol). The organic phases were combined, and distilled to ~ 3 vol. Additional dichloromethane (6 vol) was added and the distillation to 3 vol. repeated. Addition of dichloromethane, then distillation was repeated until the residual EtOH was reduced to below 1 % by NMR. The residual solution of 3 vol 35 dichloromethane was heated to 38 °C. Heptane (3 vol) was added and the mixture was stirred for 280 l h, then cooled to 20 °C over 3 h. The resulting slurry was filtered and the filter cake washed with l :1 v/v dichloromethane: heptane. The product was dried under vacuum at 45 °C to afford the product as a white solid (75 % yield).

Step j. Synthesis of l-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-pyrrolo[2,3-f]indazol-l-yl]2,2-dimethyl-propan-l-one (Cl 4)

To reactor A under nitrogen was charged 5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lHpyrrolo[2,3-fjindazole Cl3 (8.3 kg) and THF (99.4 kg). The agitator was started in Reactor A. Compound C13 dissolved and the solution was cooled to 1.7 °C. KOtBu in THF (15.9 kg) was charged to reactor A over 9 min (temp. range during addition 0.2 °C to l .6 °C). The transfer line was rinsed with THF (l.O kg) and transferred to reactor A. The contents of reactor A were stirred for 10 min at 1.6 °C. Pivaloyl chloride (3.3 kg) was charged over 32 min to reactor A with the maximum température reaching 2.3 °C. The transfer line was rinsed with THF (0.5 kg) and transferred to reactor A. The contents of reactor A were held at 0.7 °C to 2.1 °C for l h. To a drum was charged NaHCO₃ (2.3 kg) and water (32.0 kg). The contents were briefly mixed to dissolve the NaHCO₃. The contents of reactor A were warmed to 19.0 °C over 2 h 10 min. The NaHCOj solution was charged to reactor A over 10 min (max, temp. during addition 19.4 °C). MTBE (29.3 kg) was charged to reactor A. The contents of reactor A were stirred at 25 ± 5 °C for 15 min. The agitator was stopped and the phases separated for 33 min. The aqueous phase was removed. The agitator in reactor A was started. To a drum was added sodium chloride (6.2 kg) and water (26.1 kg). The drum was stirred to give a solution. The brine solution was transferred to reactor A. The contents were stirred for 19 min at 25 ± 5 °C. The agitator in reactor A was stopped and the phases settled for 20 min. The aqueous phase was removed. The agitator was started and the organic phase was concentrated by vacuum distillation to 30 L with the maximum distillation température of 26.2 °C. To reactor A was charged «-heptane (21.9 kg). The contents of reactor A were concentrated to 30 L by vacuum distillation (maximum température 25.8 °C). To reactor A was charged n-heptane (21.8 kg) over 17 min. The contents of reactor A were concentrated to 30 L by vacuum distillation (maximum température 29.3 °C). To reactor A was charged «-heptane (23.0 kg) over 16 min. The contents of reactor A were stirred at 20 ± 5 °C for 1 h. The slurry was filtered. To reactor A was charged n-heptane (11.2 kg) and transferred to the filter. This was repeated with another «-heptane (11.2 kg) rinse. The cake was dried under nitrogen pressure for 5 h and then loaded into trays and dried for 3 days to afford the product l-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-pyrrolo[2_J3-f]indazol-l-yl]-2,2dimethyl-propan-1-one (C14) as a solvaté with THF (5 wt %) by *H NMR (6.9 kg, 68 %, brown solid).

281

Step 4. Synthesis of l-[5-(4-fluorophenyl)-7-iodo-6-tetrahydropyran-4-yi-pyrrolo[2,3-f] indazoll-yl]-2,2-dimethyl-propcm-l-one (S4)

To reactor A under nitrogen was added l-[5-(4-fluorophenyl)-6-tetrahydropyran-4-ylpyrrolo[2,3-f]indazol-l-yl]-2,2-dimethyl-propan-l-one C14 (4.75 kg) and CH₂CI₂ (29 L). The agitator was started and thejacket was set at -10 °C. The solution was cooled to < 5.0 °C and Niodosuccinimide (2.73 kg) was added in three equal portions. At 3.0 °C the l^st portion was added and gave an exotherm to 4.1 °C. After 19 min the reaction température had cooled to 0.9 °C. The 2^nd portion was added at 0.9 °C with an exotherm to 2.3 °C. After 15 min, the reaction température had cooled to 1.4 °C. The 3^rd portion was added at 1.4 °C with an exotherm to 2.1 °C. CH₂C1₂ (I L) was charged to reactor A to rinse the N-iodosuccinimide. The jacket température was set at 0 °C and the reaction was stirred for 50 min with a final reaction température of 3.2 °C. To a container was charged sodium thiosulfate pentahydrate (0.85 kg) and water (14.5 L). The contents were mixed to give a solution. The sodium thiosulfate solution (room température) was charged in portions to the reaction solution (3.4 °C, jacket température 0 °C) over 8 min to give an exotherm ίο 11.6 °C. The mixture was warmed to 20 °C stirred for 15 min. The agitator was stopped to let the phases separate for 35 min. The aqueous phase was removed and back extracted with CH₂C1₂ (5 L). The mixture was stirred 10 min at 20 °C and the agitator was stopped. The phases settled for 10 min and the aqueous phase was removed. The organic phases were combined and charged back to reactor A. The agitator was started. To a container was charged KHCO3 (0.90 kg) and water (14.1 L). The contents were mixed to give a solution. The KHCO₃ aq. solution was added to reactor A and stirred for 10 min at 20 °C. The agitator was stopped and an émulsion had fonned. The phases separated ovemight and the aqueous phase was removed. The organic phase was charged back to the reactor and rinsed in with CH₂C1₂ (IL). A container was charged NaCI (3.0 kg) and potable water (12.0 L). The contents were mixed to dissolve and the brine solution was transferred to reactor A. The contents of reactor A were mixed for 10 min at 20 °C. The agitator was stopped and an émulsion had formed. After settlîng for 2 h the majority of the organic CH₂C1₂ bottom phase was removed leaving behind about 18 L of émulsion. Water (7.5 L) was added to reactor A with slow stirring (50 rpm) this diluted the brine wash from 20 wt % to approximately 12 wt %. The phases separated in 20 min and the CH₂C1₂ bottom layer was removed. The organic phase was split in half and concentrated in two flasks. Each flask was concentrated to 5 volumes. To each flask was charged MeOH (10 L) in portions and distilied to 4 volumes. To each flask was charged MeOH (4 L) and distilied to 2 volumes. The contents of each flask were cooled to 0-5 °C and stirred for 1.5 h. Contents of the two flasks were combined into one filter and filtered quickly. The filter cake was washed with 0-10 °C MeOH (2 x 5 L) and filtered fast. The cake was 282 deliquored for l h under vacuum filtration and then loaded into drying trays. The solid was dried ovemight at 45 °C in drying trays to afford S4 as a brown solid (5.75 kg, 8.98 wt % solvaté).

Préparation S5

1-(5-(4-fiuorophenyi)-6-(tetrahydro-2H-pyran-4-yl)- 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan2-yl)pyrrolo[2,3-t]indazol-l(5H)-yl)-2,2-dimethylpropan-l-one (S5)

F

Synthesis of l-(5-(4-fhiorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-7-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)pyrrolo[2,3-f] indazol-1 (5H)-yl)-2,2-dimelhylpropan-1 -one (S5)

A flask containing l-[5-(4-fluorophenyï)-7-iodo-6-tetrahydropyran-4-yl-pyrrolo[2,3f|indazol-l-yl]-2,2-dimethyl-propan-l-one S4 (0.99 g, 1.83 mmol) and Pd(dppf)Cl₂ (57 mg, 0.078 mmol) was evacuated and purged with nitrogen (x 3). m-Xylene (7.8 mL) was added and the mixture degassed. Trîethylamine (830 pL) and 4,4,5,5-Îetrainethyl-l,3,2-dioxaborolane (550 pL, 3.8 mmol) were added, and the reaction heated at 150 °C for 1 h. The mixture was cooled, and fïltered, washing with CH2CI2. The fîltrate was concentrated and the crude product mixture was purified by silica gel chromatography (Gradient: 0-5 % EtOAc in CH2CI2) to afford the product as an off-white solid (788.9 mg, 65 %). 'H NMR(400MHz, Chloroform-d) δ 9.14 (s, IH), 8.03 (s, 1H), 7.35 - 7.30 (m, 4H), 7.05 (s, IH), 4.01 (dd, J = 10.9, 3.4 Hz, 2H), 3.33 (t, J = 11.7 Hz, 2H), 3.26-3.15 (m, IH), 2.38 (qd, J = 12.6, 4.0 Hz, 2H), 1.61 (s, 9H), 1.48 (s, 12H). LCMS m/z 546.5 [M+H]⁺.

Préparation S6

283

5-/4-fluorophenyl)-7-iodo-l-(phenylsulfanyl)-6-(tetrahydro-2l·I-pyran-4-yl)-l, 5dihydropyrrolo[2,3-f] indazole (S6)

Step 1. Synthesis of l-(benzenesidfonyl)-5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-pyrrolo[2,3f] indazole (Cl5)

To a solution of 5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3-f}indazo]e C13 (10 g, 29.8 mmol) in THF (120 mL) at 0 °C was added KOtBu (4.2 g, 37.3 mmol) and the mixture stirred for 10 min. Benzene sulfonyl chloride (4.4 mL, 34.5 mmol) was added, and the mixture stirred for 1 h at 0 °C, then for an additional 1 h at room température. The mixture was concentrated in vacuo, and then saturated NH4CI and CH2CI2 were added. The organic layer was separated, and dried. Purification by silica gel chromatography (Gradient: 0-60 % CH2CI2 in EtOAc) afforded the product as a white solid, containing around 5 % of C13 (11.8 g, 83 %). ’H NMR(300MHz, Chloroform-d) δ 8.38 (t, J = 1.0 Hz, IH), 8.14 (d, J = 0.9 Hz, IH), 8.04 - 7.93 (m, 2H), 7.57 - 7.47 (m, IH), 7.46 - 7.38 (m, 2H), 7.38 - 7.30 (m, 3H), 7.15 (t, J = 0.9 Hz, IH), 6.62 (d, J = 0.8 Hz, IH), 4.08 - 3.94 (m, 2H), 3.37 (td, J = 11.8, 2.3 Hz, 2H), 2.82 (ddt, J = 11.5, 8.0, 3.9 Hz, IH), 1.98 - 1.70 (m, 5H). LCMS m/z 476.2 [M+Hf.

Step 2. Synthesis of l-(benzenesulfonyl)-5-(4-]luorophenyl)-7-iodo-6-tetrahydropyran-4-ylpyrrolo[2,3-f] indazole (S6)

To a solution of 1 -(benzenesulfonyl)-5-(4-fluorophenyl)-6-tetrahydropyran-4-ylpyrrolo[ 2,3-Q indazole C15 (151.8 g, 319.2 mmol) in CH2CL (1.52 L) cooled to 0 °C was added l-iodopyrrolidine-2,5-dione (74.5 g, 321.2 mmol), in 4 approximately equal portions over 45 min, additions were 15 min apart. After each addition a slight exotherm was observed, the

284 internai temp. rose to -2 °C. The reaction mixture was wanned to room température and stirred overnight. CH2CI2 (500 mL) was added, and the reaction was stirred for 15 min. Water (l L) was added, followed by 1 M aqueous sodium thiosulfate (200 mL). The mixture was stirred for 20 min. then the organic layer was separated, and the aqueous layer was extracted with CH2CI2 (50 5 mL). Combined organic layers were washed successively with water, saturated aqueous sodium bicarbonate, and brine (1.5 L each). The organic layer was then dried (MgSO₄), filtered and concentrated to afford a solid residue. The residue was treated with MTBE (500 mL), then stirred for 90 min. The resulting solid was isolated via filtration, washing with MTBE (2 x 200 mL) and dried under suction for 30 min. The solid was further dried under vacuum (2 mbar, 75 °C) for 30 10 min, to afford the product as pale, cream-colored crystals. l-(benzenesulfonyl)-5-(4fluorophenyl)-7-iodo-6-tetrahydropyran-4-yl-pyrrolo[2,3-f]indazole (181.4 g, 94 %). ’H NMR (400 MHz, DMSO<| δ 8.51 (d, J - 0.9 Hz, IH), 8.06 (t, J = 0.9 Hz, IH), 7.87 - 7.80 (m, 2H), 7.71 - 7.63 (m, IH), 7.62 - 7.45 (m, 6H), 7.25 (d, J = 1.0 Hz, IH), 3.96 - 3.85 (m, 2H), 3.22 (td, J = 11.8, 1.9 Hz, 2H), 2.93 (tt, J - 12.4, 3.6 Hz, IH), 2.29 (qd, J = 12,6, 4.4 Hz, 2H), 1.63 15 (dd, J = 13.5, 3.5 Hz, 2H). 19F NMR (376 MHz, DMSO-d₆) δ -111.78. LCMS m/z 602.1

285

Préparation S 7

1-(5-(4-fluorophenyl)-7-iodo-6-isopropylpyrrolo[2,3-j]indazol- 1 (5H)-yl)~2,2-dimethylpropan-1 one (S7)

Step 1. Synthesis of 5-chloro-6-(3-methylbut-1 -yn-1 -yl)-ÏH-indazole (C16)

Pd(PPh3)₂C12 (1-7 g, 2.4 mmol) was added to a nitrogen purged solution of 3-methylbut1-yne (10.7 mL, 104.6 mmol), 6-bromo-5-chloro-177-indazole C6 (10.4 g, 44.9 mmol) and Cul (497 mg, 2.6 mmol) in Et₃N (100 mL) and 1,4-dioxane (100 mL). The solution was stirred at 90 °C ovemight in a Part bottle, whereupon Celite® and methanol were added, and the mixture 10 concentrated in vacuo. Purification of the Celite® adsorbed mixture by silica gel chromatography (Gradient: 0-100 % EtOAc in heptanes) afforded the product (7.0 g, 71 %). ’H NMR(300MHz, Chloroform-d) δ 10.17 (s, IH), 8.02 (d, J= 1.1 Hz, IH), 7.80 (d, J = 0.7 Hz, IH), 7.62 (t, J = 0.9 Hz, IH), 2.88 (hept, J = 6.9 Hz, IH), 1.34 (d, J = 6.9 Hz, 6H). LCMS m/z 219.04 [M+H]⁺.

Step 2. Synthesis of N-(4-fîuoro-3-methylphenyl)-6-(3-methylbut-1 -yn-1 -yl)-\H-indazol-5-amine (Cl 7)

Z-Butanol (45 mL) and 1,4-dioxane (15 mL) were added to a flask containing 4-fluoro-3methyl-aniline (2.1 g, 16.8 mmol), 5-chloro-6-(3-methylbut-l-ynyl)-I//-indazole C16 (2.3 g,

286 .5 mmol), sodium t-butoxide (3.9 g, 40.6 mmol), and BrettPhos Pd G4 catalyst (280 mg, 0.3 mmol). The mixture was degassed and stirred under N₂ at 100 °C ovemight. The mixture was concentrated under reduced pressure, re-dissolved in dichloromethane, and washed with water. The organic layer was dried by passing through a phase separator and concentrated in vacuo. Silica gel chromatography (Gradient: 0-100 % EtOAc in heptanes) afforded the product (1.9 g, 58 %). ‘H NMR(300MHz, DMSO-ri₆) δ 12.93 (s, IH), 7.92 (s, IH), 7.52 (s, IH), 7.40 (s, IH), 7.16 (s, IH), 7.02 - 6.91 (m, IH), 6.87 - 6.71 (m, 2H), 2.75 (m, IH), 2.15 (d, J = 1.9 Hz, 3H), 1.11 (d, J = 6.9 Hz, 6H). LCMS m/z 308.2 [M+H]⁺.

Step 3. Synthesis of 5-i4fluoro-3-methylphenyl)-6-isopropyl-1.5~dihydropyi-rolo[2,3-t]indazole (C18)

A solution of Àty4-fluoro-3-methyl-phenyl)-6-(3-methylbut-l-ynyl)-lH-indazol-5-amine C17 (254 mg, 0.83 mmol) in DMSO (2.3 mL) was heated under microwave conditions at 150 °C for 30 min. The reaction mixture was poured into water (30 mL) and stirred for 4 h. The resulting solid was fîltered and dried under vacuum at 50 °C to afford the product (143 mg, 53 %). ’H NMR(300MHz, DMSO-ri₆) δ 12.58 (s, IH), 7.96 (d, J = 1.3 Hz, IH), 7.53 (d, J = 1.1 Hz, IH), 7.45 - 7.27 (m, 3H), 7.16 (d, J = 1.0 Hz, IH), 6.46 (d, J = 0.9 Hz, IH), 3.03 - 2.83 (m, IH), 2.34 (d, J = 2.0 Hz, 3H), 1.18 (d, J = 6.8 Hz, 6H). LCMS m/z 308.2 [M+Hf.

Step 4. Synthesis of l-[5-(4-fhiorophenyl)-6-isopropyl-pyrrolo[2,3-f]indazol-l-yl]-2,2-dimethylpropan-l-one (C19)

A solution of 5-(4-fluorophenyl)-6-isopropyl-lH-pyrrolo[2,3-f]indazole C18 (60 g, 204.5 mmol) in THF (600 mL) was cooled to 0 °C. KOtBu (29.8 g, 265.9 mmol) was added and the mixture allowed to stir at 0 °C for 10 min. 2,2-dimethylpropanoyl chloride (34 mL, 276.3 mmol) was added and the mixture allowed to stir at room température for 1 h. saturated NH₄C1 (640 mL) and EtOAc was added. The aqueous layer was isolated and further extracted with EtOAc. Combined organic layers were dried, and concentrated in vacuo. Purification b y silica gel chromatography (Column: 1.5 kg silica gel. Gradient: 0-30% EtOAc/Heptane) afforded the product as a yellow solid (64 g, 83 %). 'H NMR (300 MHz, Chloroform-d) δ 8.67 (t, J = 0.9 Hz, IH), 8.05 (d, J = 0.8 Hz, IH), 7.44 - 7.32 (m, 2H), 7.32 - 7.26 (m, 2H), 7.19 (t, J = 0.9 Hz, IH), 6.56 (t. J = 0.8 Hz, IH), 3.04 - 2.88 (m, IH), 1.60 (s, 9H), 1.26 (d, J = 6.8 Hz, 6H). LCMS m/z 378.17 [M+H]⁺.

Step 5. Synthesis of I-[5-(4-fluorophenyl)-7-iodo-6-isopropyl-pyrrolo[2,3-f]indazol-ï-yl]-2,2dimethyl-propan-l-one (S 7)

To a solution of l-[5-(4-fluorophenyl)-6-isopropyl-pynOlo[2,3-f]indazo!-l-yl]-2,2dimethyl-propan-1 -one C19 (71 g, 188.1 mmol) in CH₂C1₂ (710 mL) cooled to 0 °C was added 1iodopynOlidine-2,5-dione (49 g, 206.9 mmol) over 15 min. The mixture was then allowed to stir 287 at room température for 0.5 h. An additional 500 mL of CH₂Cl₂ was added. IM Na₂S₃O₄ solution (100 mL) and a saturated NaHCO₃ solution (300 mL) were also added. The organic layer was separated, washed with additional sat. NaHCO₃ (300 mL), and then dried over sodium sulfate to afford the product as a brown solid (93 g, 98 %). 'H NMR (300 MHz, Chloroform-d) δ 8.60 (t, J = 0.9 Hz, IH), 8.06 (d, J = 0.8 Hz, IH), 7.40 - 7.30 (m, 3H), 7.29 (d, J = 4.I Hz, IH), 7.07 (d, J =

0.9 Hz, IH), 3.18 (p, J = 7.2 Hz, IH), 1.61 (s, 9H), 1.39 (d, J = 7.2 Hz, 6H). LCMS m/z 504.2 [M+H]⁺.

Alternative Préparation of C18

5-(4-fliiorophenyl)-6-isopropyI-I,5-dihydropyrrolo[2,3-flindazole (Cl8)

F

Step 1. Synthesis of4-bromo-5-iodo-2-methylamline (C21)

To a solution of 5-iodo-2-methylaniline C20 (600 g, 2.6 mol) in DMF (3 L) at -6 °C was added /V-bromosuccinimide (460 g, 2.6 mol) in 5 portions over ~45 min (maintaining the température between -3 to -7 °C). The mixture was stirred at -5 to -8 °C for 55 min. The mixture 15 was quenched by addition of 0.5M Na₂S₂O₃ (200 mL) then _added to ice/water (4.8 kg) over 4 min. A slurry formed, and an exotherm to + 10 °C was observed, The mixture was diluted with additional cold water (1 L), stirred for 1 h at -10 °C, filtered and washed with water (1.5 L). The solids were dried at 45 °C under vacuum to afford the product as an off-white solid (779 g, 97 %). ’H NMR(500MHz, Chloroform-d) δ 7.25 (s, IH), 7.14 (s, IH), 3.60 (2H, s), 2.05 (3H, s). 288

Step 2. Synthesis of 5-bromo-6-iodo-\H-indazole (Cl)

To a solution of C21 (791 g, 2.5 mol) in AcOH (4.2 L) at 44 °C was added isopentyl nitrite (333 g, 2.8 mol) over 1 h. The réaction was allowed to exotherm to 55 °C, then held between 55-64 °C. The mixture was stirred at 55 °C for 30 min, then cooled to 50 °C. Ice-cold water (4.2 L) was added over 15 min while continuing to cool to 20 °C. The slurry was stirred tor 25 min at 20 °C, filtered and washed with water (2 L). The crude orange solid was dried at 50 °C under vacuum. The solid was then trîturated at room température in MeCN (2.25 L) for 30 min, filtered, and washed with MeCN (-750 mL) to afford the product as an orange solid (679 g, 83 %). 'H NMR(500MHz, DMSO-rf₆) δ 13.25 (IH, s), 8.22 (IH, s), 8.20 (IH,s), 8.05 (IH, s). Step 3. Synthesis of 5-bromo-6-(3-methylbut-l-yn-l-yl)-lH-indazole (C22)

A solution of Cl (2738 g, 8.5 mol) in DMF (10 L) was de-oxygenated with 4 x vacuum/ nitrogen cycles. The mixture was cooled to 6 °C and then diethylamine (1.54 kg, 21.1 mol) and 3-methyl-l-butyne (652 g, 9.57 mol) were added. The mixture was transferred using nitrogen pressure to an inert 20-L autoclave containing copper (I) îodîde (32 g, 168 mmol) and PdCl₂(PPh₃)₂ (H5g, 164 mmol). The autoclave was sealed, pressurized to 5 psi using nitrogen and then heated to 85 °C for 15 h. The pressure increased to 23 psi initially and then gradually decreased to 15 psi as the 3-methyl-l-butyne was consumed (the pressure stopped dropping after about 8 h, presumably indicating complété reaction). The mixture was cooled to 20 °C and then added to a mixture of 37 % hydrochloric acid (1.5 kg, 14.9 mol), water (13.7 L) and MTBE (8.7 L) at 5 °C [exotherm to 26°]. The layers were separated, and the organic layer was washed with a mixture of water (8 L) and saturated brine (2 L), and then with saturated brine (3 L). The aqueous layers were sequentially re-extracted with MTBE (5 L then 3 L). The combined organics were dried over magnésium sulfate, filtered and concentrated to dryness in vacuo. The residue was trîturated in dichloromethane (2 L) at 35 °C, gradually diluted with hexane (2 L) and cooled to 20 °C. The slurry was filtered, washed with 1:1 dichloromethane:hexane (1.5 L) and dried under vacuum at 40 °C to afford the product as a pale tan solid (1492 g, 67 %). *H NMR(500MHz, Chloroform-d) δ 10.6 (s, IH), 8.01 (s, IH), 7.98 (s,!H), 2.85 (m, IH), 1.32 (d, 9H).

Steps 4 and 5. Synthesis ofC17 and 5-(4-fluorophenyl)-6-isopropyl-\H-pyrrolo[2,3-f]indazole (C18)

To a 50 L glass reactor was added C22 (2973 g, 11.3 mol), 4-fluoroaniline (1419 g, 12.8 mol) and THF (29 L). The solution was vacuum purged with nitrogen (5 x) and cooled to 3 °C. Sodium i-butoxide (3.47 kg, 36 mol) was added in 1 kg _pt)rti_ons over 20 min with a resulting heat rise to 16 °C. The solution was vacuum purged with nitrogen (5 x) and cooled to 11 °C. iBuXPhos Pd G1 MTBE cataiyst (200 g, 0.2 mol) was added în 3 portions over 1 h. An exotherm 289 to 33 “C over 2 h was observed. The contents were stirred overnight - coolîng to room température. HPLC analysis indicated conversion to C17. The solution was diluted with hexanes (4 L) and cooled to 3 °C. Acetic acid was added over 1 h (exotherm to 20 °C). Water (8 L) was added and the contents stirred, then settled. The lower layer was removed, and the upper layer concentrated by vacuum distillation to approx. 10 L. The solution was diluted with méthanol (25 L) and heated overnight to about 55 °C. The solution was concentrated by vacuum distillation to about 10 L and cooled to 16 °C. The solids were collected by filtration and washed with cool méthanol (4 L) and dried in a vacuum oven to provide the product C1S as a brown solid. (2.52 kg, 76 % yield).

Préparation S8

1-(5-( 4-fluorophenyl)-6-isopropyl- 7-(4,4,5,5-tetrameth.yl-l ,3,2-dioxaborolan-2-yl)pyrrolo[2,3f]indazol-l(5H)-yl)-2,2-dimethylpropan-l-one (SS)

Synthesis of 1 -(5-(4-fluorophenyl)-6-isopropyl-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)pyrrolo[2,3-f] indazol-1 (5 H)-yl)-2,2-dimethylpropan-l -one (S8)

A flask containing l-[5-(4-fluorophenyI)-7-iodo-6-isopropyl-pyrrolo[2,3-f]mdazol-l-yl]2,2-dimethyl-propan-l-one S7 (3.95 g, 7.7 mmol) and Pd(dppf)C12 (230 mg, 0.31 mmol) was évacuaied and purged with nitrogen. m-Xylene (31 mL) was added and the mixture degassed. Triethylamine (3.4 mL) and 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (2.4 mL, 16.5 mmol) were added and the mixture heated at 150 °C for 3 h. The solution was cooled and filtered, washing with dîchloromethane, then purified by silica gel chromatography (Gradient: 25-100% dîchloromethane in Heptane) to afford the product as a pale orange solid (3.03 g, 77 %). ’H NMR(400MHz, Chloroform-d) δ 9.15 (s, IH), 8.02 (d, J = 1.3 Hz, IH), 7.37 - 7.26 (m, 4H), 7.05 (s, IH), 3.23 (hept, J = 5.9 Hz, IH), 1.61 (s, 9H), 1.47 (s, 12H), 1.39 (dd, J = 7.1, 1.5 Hz, 6H). LCMS m/z 504.4 [M+H]⁺.

290

Préparation S9

5- (4-fluorophenyl)- 7-iodo-6-isopropyl- l-tosyl-1, 5-dihydropyrrolo[2,3-f]indazole (S 9)

Step 1. Synthesis of 5-(4-fluorophenyl)-6-isopropyl-l-(p-tolylsulfonyl)pyrrolo[2,3-f] indazole (C23)

To a solution of 5<4-fluorophenyl)-6-isopropyl-lH-pyrrolo[2,3-f]indazole C18 (5.13 g, 17.5 mmol) in DMF (55 mL) was cooled to 0 ^ÛC under N₂. NaH (1.05 g of 60 % w/w, 26.3 mmol in minerai oil) was added. Upon stirring for 1 h at room température, 4methylbenzenesulfonyl chloride (5.0 g, 26.2 mmol) was added and the mixture was allowed to stir at 0 °C for 1 h. Water was added (- 100 mL) and the mixture was allowed to stir at room température. The resulting precipitate was collected via filtration, washed with water, then heptane. The solid was dissolved in CH2CI2, and filtered through a phase separator. The solution of product in CH2CI2 was dried over Na₂SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (Gradient: 0-50 % EtOAc/heptane) followed by a second silica gel chromatography (Gradient: 0-20 % EtOAc/CH₂C12) afforded the product as a pale yellow solid (5.52 g, 68 %). ’H NMR(300MHz, Chloroform-d) δ 8.34 (s, IH), 8.13 (d, J = 0.9 Hz, 1 H), 7.85 (d, J = 8.4 Hz, 2H), 7.44 - 7.23 (m, 4H), 7.22 - 7.16 (m, 2H), 7.13 (d, J = 0.9 Hz, IH), 6.59 (d, J = 0.8 Hz, IH), 2.95 (p, J = 6.8 Hz, IH), 2.33 (s, 3H), 1.26 (d, J = 6.8 Hz, 6H). LCMS m/z 448.36 [M+Hf.

Step 2. Synthesis oj5-(4-fluorophenyl)-7-iodo-6-isopropyl-l-(p-tolylsulfonyl)pyrrolo[2,3fj indazole (S9)

To a solution of 5-(4-fluorophenyl)-6-isopropyI-l-(p-tolylsulfonyl)pyrrolo[2,3-f]indazole C23 (5.52 g, 11.8 mmol) in CH2CI2 (55 mL) was added iodopyrrolidine-2,5-dione (2.92 g, 12.9 mmol) and allowed to stir at room température for 2 h. The mixture was then purified by silica gel chromatography (Gradient: 0-20 % EtOAc in CH₂C1₂). The product fractions were combined, concentrated and dissolved in CH2CI2. The solution was washed with 1 M sodium thiosulfate, dried over Na₂SO₄, filtered and evaporated to afford the product as a pale yellow solid (5.80 g, 83 %). ‘H NMR(300MHz, Chloroform-d) δ 8.32 - 8.22 (m, IH), 8.14 (d, J = 0.9 Hz, IH), 7.89

291 (d, J = 8.3 Hz, 2H), 7.27 (m, 4H), 7.26 - 7.13 (m, 2H), 7.02 (d, J = 0.9 Hz, IH), 3.17 (p,J = 7.2 Hz, IH), 2.34 (s, 3H), l .39 (d, J = 7.1 Hz, 6H). LCMS m/z 574.3 [M±H]⁺.

Préparation S10

5-(4-fluorophenyl)-7-iodo-6-isopropyl-l-((2-(trimethylsilyl)ethoxy)methyl)-l, 5dihydropyrrolof 2,3-j]indazole (SI 0)

ci 7 C24 Sio

Step 1. 5-(4-fluorophenyl)-7-iodo-6-isopropyl-lH-pyrrolo[2,3-j]indazole (C24) l-iodopynOlidine-2,5-dione (3.4 g, 15 mmol) în CH2CI2 (104 mL) was added dropwise to a solution of 5-(4-fluorophenyl)-6-isopropyl-lH-pyrrolo[2,3-f]indazole C17 (4.0 g, 13.6 mmol) in CH2CI2 (104 mL) at 0 °C. The mixture was stirred _at room température for 60 min. The reaction mixture was then quenched with 1 M sodium thiosulfite. Water was added and the mixture was extracted with CH2CI2 (3 x). The organic phases were combined, fdtered through a phase separator and concentrated in vacuo. Silica gel chromatography (Gradient: 0-20 % of EtOAc in CH2CI2) afforded the product as a yellow solid (4.17 g, 73 %). ’H NMR (400 MHz, Chlorofonn-d) δ 8.05 (d, J = 1.1 Hz, IH), 7.50 (t, J = 1.1 Hz, IH), 7.38 - 7.31 (m, 2H), 7.31 7.24 (m, 2H), 7.11 (d, J = 1.1 Hz, IH), 3.15 (hept, J = 7.2 Hz, IH), 1.38 (d, J = 7.2 Hz, 6H). LCMS m/z 420.1 [M+H]⁺.

Step 2. 2-[]5-(4-fluorophenyl)-7-iodo-6-isopropyl-pyrrolo[2.3-f]indazol-1 -yl]methoxy]ethyltrimethyl-silane (SI 0)

To a solution of 5-(4-fluorophenyl)-7-iodo-6-isopropyl-lH-pyrrolo[2,3-f|mdazole C24 (1.08 g, 2.6 mmol) and nBu₄NBr (41 mg, 0.13 mmol) in CH₂C1₂ (5 mL) at 0 °C was added KOH (4.5 mL, 163.9 mmol) and SEM-C1 (510 pL, 2.9 mmol). The mixture was allowed to stir at room température ovemight. Water and CH2CI? were added and phases were separated on a phase separator. Silica gel chromatography (Eluent: Ethyl acetate/ heptanes) afforded the product (1.2 g, 86 %). LCMS m/z 550.2 [M+H]\ Préparation SU l-(5-(4-fluorophenyl)-7-iodo-6-(l-methoxy-2-methylpropan-2-yl)pyrrolo[2,3-f] indazol-1 (5H)292 yl)-2,2-dimethylpropan-l -one (SI 7)

Step 1. Synthesis of 5-chloro-6-(4-methoxy-3,3-dimethyl-but-l-ynyl)-lH-indazole (C25)

A solution of 6-bromo-5-chloro-lH-indazole C6 (5.2 g, 22.46 mmol), PPh₃ (355 mg, 1.4 mmol), Pd(PPh₃)₂Cl₂ (473 mg, 0.67 mmol), Cul (257 mg, 1.3 mmol) and Et₃N (40 mL) in 1,4dioxane (40 mL) was purged with nitrogen. 4-methoxy-3,3-dimethyl-but-l-yne (3.5 g, 31.5 mmol) was added and the reaction was heated at 110 °C for 1.5 h. A white solid precipitated upon cooling. The reaction was filtered through Celite®, washing with EtOAc. The fïltrate was concentrated and purified by silica gel chromatography (Gradient: 0-80 % EtOAc/ heptane) to afford the product as a brown solid (3.5 g, 59 %). ^!H NMR(300 MHz, Chloroform-d) δ 10.27 (s, IH), 8.00 (s, IH), 7.78 (d, J = 0.5 Hz, IH), 7.63 (s, IH), 3.49 (s, 3H), 3.42 (s, 2H), 1.38 (s, 6H). LCMS m/z 263.1 [M+H]⁺.

Step 2. Synthesis of N-(4-fluorophenyl)-6-(4-methoxy-3,3-dimethyl-hut-l-ynyl)-lH-indazol-5amine (C26)

A suspension of 5-chloro-6-(4-methoxy-3,3-dimethyI-but-l-ynyl)-lH-indazole C25 (4.3 g, 16.37 mmol), 4-fluoroaniline (2.5 mL, 26.4 mmol), NaOtBu (4.09 g, 42.6 mmol) in tBuOH (60 mL) were purged with nitrogen. tBuXPhos Pd G1 (563 mg, 0.82 mmol) was added and the mixture purged with nitrogen for an additional 10 min. The mixture was heated at 90 °C for 1 h. An additional 1.4 % of tBuXPhos Pd G1 catalyst (-150 mg) was added, and the mixture heated 293 to reflux for another 1 h. Then a further portion of tBuXPhos Pd Gl(80mg) catalyst was added, and the mixture heated to reflux for 1.5 h. The mixture was concentrated in vacuo, and then saturated NH4CI and EtOAc were added. The layers were separated and the aqueous layer extracted with forther EtOAc. Combined organic layers dried, and concentrated in vacuo. Purification by silica gel chromatography (Gradient: 0-S0 % EtOAc/ heptane) afforded the product. LCMS m/z 338.0 [M+H]Ù

Step 3. Synthesis of 5-(4-fiuorophenyl)-6-(2-methoxy-l,l-dimethyl-ethyl)-lH-pyrrolo[2,3Jjindazole (C27)

A solution of C26 in DMSO (26 mL) was heated at 160 °C for 2 h. Upon cooling, 50 % saturated NaHCO₃ solution (120 mL) was added. The mixture was extracted with EtOAc (x 2). The organic layer was concentrated to afford the product as a grey solid which was used without further purification (5 g, 91 %). NMR (300MHz, Chloroform-d) δ 9.89 (s, IH), 7.99 (s, IH), 7.54 (t, J = 1.1 Hz, IH), 7.47 - 7.36 (m, 2H), 7.28 - 7.19 (m, 2H), 6.88 (s, IH), 6.57 (d, J = 0.7 Hz, IH), 3.27 (s, 3H), 3.23 (s, 2H), 1.33 (s, 6H). LCMS m/z 422.3 [M+H]⁺.

Step 4. -[5-(4-fluorophenyl)-6-(2-methoxy-l, 1 -dimethyLethyl)pyrrolo[2.3-f indazol-I -yl]-2_S2dimethyl-propan-l-one (C28)

To a solution of 5-(4-fluorophenyl)-6-(2-methoxy-l,l-dimethyl-ethyl)-lH-pyrrolo[2,3f]indazole C27 (6 g, 17.8 mmol) în THF (70 mL) cooled to 0 °C was added KOtBu (2.7 g, 24.1 mmol) and the mixture stirred for 10 min. 2,2-dimethyîpropanoyl chloride (2.9 mL, 23.6 mmol) was added and the reaction allowed to stir for an additional 1 h. Sat. NH₄C1 and EtOAc were added. The layers were separated, and the aqueous layer extracted with additional EtOAc. Combined EtOAc layers were dried, and concentrated. Silica gel chromatography (Gradient: 040 % EtOAc in heptanes) afforded the product as a bright yellow solid (5.2 g, 69 %). 'H NMR (300 MHz, Chloroform-d) δ 8.64 (t, J = 0.8 Hz, IH), 8.01 (d, J = 0.7 Hz, IH), 7.47 - 7.36 (m, 2H), 7.32 - 7.23 (m, 2H), 6.86 (s, IH), 6.65 (d, J = 0.7 Hz, IH), 3.27 (s, 3H), 3.23 (s, 2H), 1.59 (d, J = 2.9 Hz, 9H), 1.33 (s, 6H). LCMS m/z 422.3[M+l]+.

Step 5. Synthesis of I-[5-(4-fluorophenyl)-7-iodo-6-(2-methoxy-l,l-dimethyl ethyï)pyrrolo[2,3f]indazol-l-yl]-2,2-dimethyl-propan-l-one (SU)

To a solution of l -[5-(4-fluorophenyl)-6-(2-methoxy-1, l -dimethyl-ethyl)pyrrolo[2,3f]indazol-l-yl]-2,2-dîmethyl-propan-l-one C28 (4.2 g, 9.96 mmol) in CH2CI2 (42 mL) at 0 °C was added l-iodopyrrolîdine-2,5-dione (2.47 g, 10.98 mmol). The mixture was allowed to stir for I h at room température. CH2CI2 (100 mL) was added, followed by IN Να₂8₃θ4 and NaHCO₃. The organic layer was washed with additional NaHCO₃, dried and concentrated down to afford the product as a yellow solid (5.2 g, 95 %). ’H NMR (300 MHz, Chloroform-d) Ô 8.67

294 (t, J = 0.8 Hz, IH), 8.03 (d, J = 0.8 Hz, IH), 7.42 - 7.32 (m, 2H), 7.27 - 7.17 (m, 2H), 6.82 (d, J = 0.9 Hz, IH), 3.67 (s, 2H), 3.26 (s, 3H), 1.60 (s, 9H), 1.42 (s, 6H). LCMS m/z 548.1 [M+H]⁺.

Compound1

4-[5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3-f]indazol- 7-yl]benzoic acid

Step 1. Synthesis of methyl 4-[l-(benzenesulfonyl)-5-(3,4-difluorophenyl)-6-tetrahydropyran-4yl-pyrrolo[2,3-f]indazol- 7-yl]benzoate (C29)

A mixture of l-(benzenesulfonyl)-5-(3,4-difluorophenyl)-7-iodo-6-tetrahydropyran-4-yl10 pyrrolo[2,3-f]indazole SI (5000 mg, 7.6 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)benzoate (4 g, 15.3 mmol) and PdCl₂(dppf)₂ (300 mg, 0.37 mmol) was placed in a vial and purged with nitrogen. 1,4-dioxane (30 mL) and sodium carbonate (11 mL of 2 M, 22.0 mmol) were added and the mixture purged with nitrogen for 10 min. The mixture was then heated at 90 °C under microwave conditiond for 60 min. Water and CH₂C1₂ were added and the 15 aqueous and organic layers separated. The organic layer was concentrated in vacuo and the crude product mixture was purified by silica gel chromatography (Eluent: Ethyl acetate/CH₂Cl₂) to afford the product as a beige solid (4 g, 83 %). ’H NMR (400 MHz, DMSO) δ 8.49 (s, 1 H), 8.22 (d, J = 7.7 Hz, 2H), 7.91 (d, J = 10.3 Hz, 2H), 7.71 (qt, J = 15.0, 8.4 Hz, 6H), 7.53 (t, J = 8.1 Hz,

295

3H), 7.33 (s, IH), 3.94 (s, 3H), 3.73 (d, J = 10.7 Hz, 2H), 3.14 (d, J = 12.1 Hz, 2H), 3.01 (dt, J = 10.9,6.6 Hz, IH), 1.73 - 1.53 (m, 4H).

Step 2. Synthesis of methyl 4-[5-(3,4-dijluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3f]indazol-7-yl]benzoate (C30)

To a solution of methyl 4-[l-(benzenesulfonyl)-5-(3,4-difluorophenyl)-6· tetrahydropyran-4-yl-pyrrolo[2,3-f]indazol-7-yl]benzoate C29 (405 mg, 0.65 mmol) in MeCN (3.6 mL) was added HCl (1.6 mL of 4 M, 6.4 mmol) in 1,4-dioxane. The mixture was heated to 70 °C ovemight. Water (1.1 mL) was added and the mixture heated to 70 °C for an additional 30 min. Water and CH7CI2 were added and the phases were separated on a phase separator. The organic layer was concentrated in vacuo. Purification by reversed-phase chromatography (Column: Cl 8. Gradient: 0-100 % MeCN in water with 0.1 % fonnic acid) afforded the product, which was used in the subséquent step without further purification. (175 mg, 56 %). LCMS m/z 488.4 [M+H]⁺.

Step 3. Synthesis of 4-[5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3-f]indazol7-yl]benzoic acid (1)

A solution of methyl 4-(5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3f]indazol-7-yl]benzoate C30 (291 mg, 0.6 mmol) in THF (7.5 mL) and MeOH (3.8 mL) was treated with NaOH (3 mL of 1 M, 3.0 mmol) and heated to 50 °C for 30 min. The réaction mixture was cooled and the pFI adjusted to 3 by addition of 2 N HCl. Water and CH₂C1₂ were added and the phases were separated on a phase separator. The organic layer was concentrated in vacuo and the mixture purified by reversed-phase chromatography (Column: Cl8. Gradient: ΟΙ 00 % MeCN in water with 0.1 % fonnic acid). The product was triturated with MBTE, then dissolved in CHzCb/MeOH. 200 mg MP-TMT resin (Pd scavenger) was added and the mixture stirred for 3 h. The mixture was filtered, and washed with CH2CI2 and MeOH, followed b y flushing with heptanes and MBTE. An additional purification by reversed-phase chromatography (Column: Cl8. Gradient: 0-100 % MeCN in water with 0.1 % fonnic acid), then drying under vacuum afforded the product (125.4 mg, 44 %). ^lH NMR (400 MHz, DMSO-î/ô) δ 13.02 (s, IH), 12.61 (s, IH), 8.12 (d, J = 7.8 Hz, 2H), 8.01 (s, IH), 7.88 (t, J = 9.6 Hz, IH), 7.75 (q, J = 9.3 Hz, IH), 7.63 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.9 Hz, IH), 7.24 (s, IH), 7.17 (s, IH), 3.84 - 3.59 (m, 2H), 3.13 (s, 2H), 3.00 (s, IH), 1.68 (d, J = 7.6 Hz, 4H). LCMS m/z 474.4 [M+H]⁺.

Compound 2-5

Compounds 2-5 (Table 2) were prepared in two or three steps from intennediate SI from the appropriate boronic ester or boronic acid according to the method described for compound 1. Any modifications to methods are noted in Table 2 and accompanying footnotes. In some cases, 296 the Suzuki coupling reaction is performed using XPhos Pd G3 as the catalyst and K₃PO₄ as the base.

Table 2. Method ofpréparation, structure, physicochemical data for compounds 2-5

Compound	Method/Product	Boronic acid or ester	H NMR; LCMS m/z [M+Hf
2	Compound 1J from SI %-ΟΗ JM pJJ H / N /--\ \\ L I JJ p MJ %/ + F	0x,0Me -Q ,B^ HO OH	‘H NMR(400MHz, DMSOd]) δ 13.38 (s, IH), 12.61 (s, IH), 8.02 (s, IH), 7.95 (d, J = 8.1 Hz, IH), 7.87 (d, J = 10.0 Hz, IH), 7.79 - 7.62 (m, 2H), 7.55 - 7.43 (m, IH), 7.21 (s, IH), 7.06 (s, IH), 3.78 - 3.67 (m, 2H), 3.12 (t, J = 11.9 Hz, 2H), 2.91 (t, J = 12.2 Hz, IH), 1.76 - 1.50 (m, 4H). LCMS m/z 492.2 [M+H]“.
3	Compound 1! from SI Fx___ O en 1 T >--( O N λ---7 fj U/F F	O^^OMe Ijk .OH F B OH	‘H NMR (400 MHz, DMSO-^) δ 13.45 (s, IH), 12.61 (s, IH), 8.02 (s, IH), 7.91 - 7.83 (m, 2H), 7.81 7.71 (m, 2H), 7.64 - 7.58 (m, IH), 7.52 - 7.45 (m, IH), 7.21 (d, J = 16.2 Hz, 2H), 3.80 - 3.71 (m, 2H), 3.16 - 3.07 (m, 2H), 2.98 (t, J = 12.2 Hz, IH), 1.74 1.56 (m, 4H). LCMS m/z 492.4 [M+H]+.
4	Compound F from SI 0. VOH \/ O H f^ J Ύ lVJ p fl JAf F	0.^.0 Me Fx^Jx IM HO'B'OH	’HNMR (400 MHz, DMSO-iZft) δ 13.30 (s, IH), 12.64 (s, IH), 8.08-7.99 (m, 2H), 7.86 (t, J = 9.2 Ηζ,ΙΗ), 7.76 (q, J = 9.3 Ηζ,ΙΗ), 7.50- 7.39 (m, 3H), 7.29 (s, IH), 7.17 (s, IH), 3.75 (d, J = 11.2 Hz, 2H), 3.20 - 3.09 (m, 2H), 3.08 -2.96 (m, IH), 1.761.57 (m,4H). LCMS m/z 492.3 [M+Hf.

297

Compound	Met h od/Pro duct	Boronic acid or ester	Ή NMR; LCMS m/z [M+H]
5	Compound ll from SI J O CH H N/---v Kx T £ 2—( p F	F O HO''B'OH	’HNMR (400 MHz, DMSO-4)5 13.41 (s, IH), 12.60 (s, IH), 8.01 (s, IH), 7.93 (d,J = 6.9 Hz, IH), 7.89-7.82 (m, IH), 7.797.69 (m, 2H), 7.53-7.44 (m, 2H), 7.18 (d, J = 5.8 Hz, 2H), 3.78 - 3.69 (m, 2H), 3.12 (t, J = 11.2 Hz, 2H), 2.94 (t, J = 12.4 Hz, IH), 1.74-1.55 (m,4H). LCMS m/z 492.4 [M+H] L

Step l. XPhos Pd G3, K3PO4 in l,4-dioxane at 85 °C for l h. Step 2. 4 M HCl, MeCN at 70 °C; Step 3. 2 M NaOH in THF/MeOH at 55 °C ²' Ester hydrolysis and sulfonamide de-protection performed in a single step with 2 M NaOH in

MeOH/THF at 55 °C

Compound 6

4-]5-(3-fliiorophenyl)-6-methyl-lH-pyrrolo[2.3f]indazol-7-yl]benzoic acid (6)

Step L Synthesis of methyl 4-[1 -(2,2-dimethylpropanoyl)-5-(3-fluorophenyl)-6-methylpyrrolo[2,3-f] indazol- 7-yl] benzoate (C31)

A mixture of 1-(5-(3-fluorophenyl)-7-iodo-6-methyl-pyrrolo[2,3-f]indazol-l-yl]-2,2dimethyl-propan-l-one S2 (38 mg, 0.08 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)benzoate (41 mg, 0.16 mmol) and Pd(dppf)Cl₂ (3 mg, 0.004 mmol) in a reaction vial were placed under a nitrogen atomosphere. 1,4-Dioxane (500 pL) and sodium carbonate (25 mg, 0.24 mmol) were added and the mixture purged with nitrogen. The reaction was heated at 90 °C for 60 min. Water and CH₂C1₂ were added. The organic layer was passed

298 through a phase separator and concentrated in vacuo to afford the crude product which was used in the subséquent step without further purification (37.4 mg, [00 %). LCMS m/z 484.5 [M+H]⁺.

Step 2. Synthesis of 4-[5-(3-fluorophenyl)-6-methyl-lH-pyrrolo[2,3-f]indazol-7-yl]benzoic acid (6)

Sodium hydroxide (1000 pL of I M, 1.0 mmol) was added to a solution of methyl 4-[l(2,2-dimethylpropanoyl)-5-(3-fluorophenyl)-6-methyl-pyrrolo[2_J3-f]indazol-7-yl]benzoate C31 (37.4 mg, 100 %) in methanol (2 mL) and THF (2 mL). The mixture was heated at 50 °C for 2 h. The reaction mixture was concentrated in vacuo, acîdified with acetic acid and diluted with DMSO (2 mL). Purification by reversed-phase HPLC (Method: Cl8 Waters Sunfire column (30 xl50 mm, 5 micron). Gradient: 10-100 % MeCN in H₂O with 0.2 % formic acid) afforded the product (19.3 mg, 62 %). ’H NMR(300MHz, DMSO-<4) δ 12.92 (s, IH), 12.69 (s, IH), 8.15 8.07 (m, 2H), 8.05 (d, J = 1.0 Hz, 1 H), 7.78 - 7.66 (m, 3H), 7.64 (t, J = 1.1 Hz, IH), 7.56 (dt, J = 10.0, 2.3 Hz, IH), 7.49 - 7.37 (m, 3H), 2.40 (s, 3H). LCMS m/z 386.3 [M+H]⁺.

Compounds 7-10

Compounds 7-10 were prepared in two steps from S2 or S3 and the appropriate boronic acid or boronic ester as described for compound 6.

Table 3. Method of préparation, structure, physicochemical data for compounds 7-10

Compound	Method/Product	Boronic acid or ester	'H NMR; LCMS m/z [M+H]’
7	Compound 61 from S2 VOH O H /N fl h^/^F	.B. O O	'HNMR(300MHz, DMSO-d6)S 12.95 (s, IH), 12.60 (s, IH), S.04 (d, J = LO Hz, IH), 8.01 (d, J= 1.8 Hz, IH), 7.89 (dd, J = 7.9, 1.8 Hz, IH), 7.75-7.61 (m, IH), 7.57 (dt, J = 10.0, 2.3 Hz, 1 H), 7.52 -7.44 (m, 3H), 7.44-7.34 (m, IH), 7.13-7.04 (m, IH), 2.27 (s, 3H), 2.18 (s, 3H). LCMS m/z 400.3 [M+H]+.
8	Compound 6' from S2	O^.OPJle A Y^F JJ Cj	’H NMR (300 MHz, DMSO-c/6)Ô 13.27 (s, IH), 12.68 (s, IH), 8.05 (d, J = 1.0 Hz, 11-1),7.94 (dd, J = 7.9, 1.7 Hz, IH), 7.87 (dd, .1 - 10.7, 1.6 Hz, IH), 7.80 7.66 (m, 2H), 7.58 (dt, J = 9.9, 2.2 Hz, IH), 7.497.38 (m, 4H), 2.30 (d, J = 1.4 Hz, 3H). LCMS m/z

299

Compound	Method/Product	Boronic acid or ester	‘H NMR; LCMS m/z [M+H]1
	Ox %-OH O H F vX XV- fl		404.11 [M+H]'.
9	Compound 6‘ from S2 Ox y-on (y OMe iXXv- A.	O^O Me ^OMe ,BX O O	'il NMR (300 MHz, DMSO-Z) δ 13.02 (s, IH), 12.61 (s, IH), 8.02 (d, J = 1.0 Hz, 1 H), 7.74- 7.65 (m, 3H), 7.59-7.51 (m, 2H), 7.47 - 7.36 (m, 3H), 7.29 7.25 (m, IH), 3.85 (s, 3H), 2.22 (s, 3H). LCMS m/z 416.37 [M+H]’.
10 1» W ’ Γ-	Compound 6‘from S3 Ox y-OH θ H nx JL Γ Vf p X W^Z^F	O^OMe ô R ^0__0^	’H NMR (300 MHz, DMSOZ)Ô 13.00 (s, IH), 12.60 (s, IH), 8.16 - 8.05 (m, 2H), 8.01 (d, J = LO Hz, IH), 7.78 - 7.68 (m, 1 H), 7.68 -7.60 (m, 2H), 7.60 - 7.46 (m, 2H), 7.46 7.40 (m, IH), 7.24 (t, J = 1.1 Hz, IH), 7.15 (d, J = 1.1 Hz, IH), 3.73 (d, J = 11.3 Hz, 2H), 3.18-2.94 (m, 3H), 1.75 - 1.57 (m, 4H). LCMS m/z 456.37 [M+H]-.

Purification by reversed-phase HPLC (Method: Cl 8 Waters Sunfire column (30 xl 50 mm, 5 micron). Gradient: 10-100 % MeCN in H₂O with 0.2 % formic acid)

300

Compound 11

3-[ÿ-(4-fluoro-3-methyl-phenyl)-6~isopropyl-lH-pyrrolo[2,3-fj indazol- 7-yl]benzoic acid (11)

Step 1. Synthesis of 5-chloro-6-(3-methylbut-l-yn-l-yl)-lH-indazole (C32) i-ButanoI (45 mL) and 1,4-dioxane (15 mL) were added to a flask containing 4-fluoro-3methyl-aniline (2.1 g, 16.8 mmol), 5-chloro-6-(3-methylbut-l-ynyl)-i//-indazole C16 (2.3 g, 10.5 mmol), sodium t-butoxide (3.9 g, 40.6 mmol), and BrettPhos Pd G4 catalyst (280 mg, 0.3 mmol). The mixture was degassed and stirred under N₂ at 100 °C ovemight. The mixture was 10 concentrated under reduced pressure, re-dîssolved in dichloromethane, and washed with water. The organic layer was dried by passing through a phase separator and concentrated in vacuo. Silica gel chromatography (Gradient: 0-100 % EtOAc in heptanes) afforded the product (1.9 g, 58 %). ^lH NMR(300MHz, DMSO-rf₆) Ô 12.93 (s, IH), 7.92 (s, IH), 7.52 (s, IH), 7.40 (s, IH), 7.16 (s, IH), 7.02 - 6.91 (m, IH), 6.87 - 6.71 (m, 2H), 2.75 (m, IH), 2.15 (d, J = 1.9 Hz, 3H), 15 1.11 (d, J = 6.9 Hz, 6H). LCMS m/z 308.2 [M+H]⁺.

301

Step 2. Synthesis of 5-(4-fluoro-3-methylphenyl)-6-isopropyl-l,5-dihydropyrrolo[2,3-j]indazole (C33)

A solution of A^r-(4-fluoro-3-methyl-phenyl)-6-(3-methylbut-l-ynyl)-lH-indazol-5-amine C32 (254 mg, 0.83 mmol) in DMSO (2.3 mL) was heated at 150 °C under microwave conditions for 30 min. The reaction mixture was poured into water (30 mL) and stirred for 4 h. The resulting solid was fîltered and dried under vacuum at 50 °C to afford the product (143 mg, 53 %). 'H NMR (300MHz, DMSO-î/₆) δ 12.58 (s, IH), 7.96 (d, J = ] .3 Hz, IH), 7.53 (d, J = I.l Hz, IH), 7.45 - 7.27 (m, 3H), 7.16 (d, J = 1.0 Hz, IH), 6.46 (d, J = 0.9 Hz, IH), 3.03 - 2.83 (m, IH), 2.34 (d, J = 2.0 Hz, 3H), 1.18 (d, J =6.8 Hz, 6H). LCMS m/z 308.2 [M+H]\ Step 3. Synthesis of 5-(4fhioro-3-methyl-phenyl)-7-iodo-6-isopropyl-lH-pyn'o!o[2,3-f]indazole (C34) l-iodopyrrolidine-2,5-dione (285 mg, L267 mmol) and 5-(4-fluoro-3-methyl-phenyl)-6isopropyl-lH-pyrrolo[2,3-f]indazole C33 (420 mg, 1.31 mmol) were diluted with dichloroethane (12.6 mL) and the mixture was flushed with nitrogen. The mixture was allowed to stir at room température for 30 min. Celite® was added and the mixture was concentrated in vacuo. Purification of the Celite® adsorbed crude mixture by silica gel chromatography (Gradient: 0-50% EtOAc în heptane) afforded the product (194.6 mg, 34%). ’H NMR (300 MHz, DMSO-ri₆) δ 12.73 (s, IH), 8.02 (t, J = L3 Hz, IH), 7.48 - 7.29 (m, 4H), 7.09 (t, J = 0.8 Hz, IH), 3.04 (p, J = 7.1 Hz, IH), 2.33 (d, J = 2.0 Hz, 3H), 1.34 (dd, J = 7.1, 1.3 Hz, 6H). LCMS m/z 434.1 [M±H]⁺.

Step 4. Synthesis of tert-butyl 5-(4-fluoro-3-methyl-phenyl)-7-iodo-6-isopropyl-pyrrolo[2,3f] indazole-I-carboxylate (C35)

To a solution of 5-(4-fiuoro-3-methyl-phenyl)-7-iodo-6-isopropyl-lH-pyrrolo[2,3f]indazole C34 (200 mg, 0.5 mmol) in CH₂C1₂ (6 mL) was Boc₂O (150 mg, 0.7 mmol), DIPEA (180 μL, 1.0 mmol) and DMAP (13.0 mg, 0.11 mmol). The mixture was allowed to stir at 25 °C for 16 h. Silica gel chromatography (Gradient: 0-40 % EtOAc in heptane) afforded the product (240 mg, 97 %) as mixture of regioisomers which were used in the subséquent step without separating.

*H NMR (400 MHz, Chloroform-d) Minor: δ 8.39 (d, J = 1.2 Hz, IH), 7.52 (t, J = 1.3 Hz, IH), 7.02 - 6.87 (m, 3H), 6.62 (d, J = 1.3 Hz, IH), 2.14 (dd, J = 4.9, 2.0 Hz, 3H), 1.50 (s, 9H), 1.15 (ddd, J = 10.3, 7.2, 3.4 Hz, 6H). Major: δ 7.99 (s, IH), 7.90 (d, J = 0.9 Hz, IH), 7.02 - 6.87 (m, 3H), 6.62 (d, J = 1.3 Hz, IH), 2.93 (p, J = 7.2 Hz, IH), 2.14 (dd, J = 4.9, 2.0 Hz, 3H), 1.56 (s, 9H), 1.15 (ddd, J = 10.3, 7.2, 3.4 Hz, 6H).

Step 5. Synthesis of methyl 3-[5-(4-fluoro-3-methyl-phenyl)-6-isopropyl-lH-pyrrolo[2,3f]indazol-7-yl]benzoate (C36)

302

A mixture of tert-butyl 5-(4-fluoro-3-methyl-phenyI)-7-iodo-6-isopiOpyl-pyrrolo[2,3f]indazole-l-carboxylate C35 (75 mg, 0.08 mmol), methyl 3-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)benzoate (30 mg, 0.12 mmol) and Pd(dppf)Cl₂ (3 mg, 0.004 mmol) were placed in a vial under nitrogen. DMF (400 pL) and sodium carbonate (115 pL of 2 M, 0.23 5 mmol) were added and the reaction aiiowed to stir overnight at S0 °C. The mixture was concentrated in vacuo. Water and CH₂C1₂ were added, and the phases were separated on a phase separator. Purification on silica gel (Eluent: Ethyl acetate in heptanes) afforded the product (14 mg, 42 %). LCMS m/z 442.35 [M+l]⁺.

Step 6. Synthesis of 3-[5-(4-fhioro-3-methyl-phcnyl)-6-isopropyl-lH-pyn'olo[2,3-f]indazol-710 yl]benzoic acid (11)

To a solution of methyl 3-[5-(4-fIuoro-3-methyl-phenyl)-6-isopropyl-lH-pyrrolo[2,3f]indazol-7-yl]benzoate C36 (10 mg, 0.02 mmol) in MeOH (0.5 mL) and THF (1 mL) was added NaOH (500 pL of 1 M, 0.5 mmol) and the reaction was heated at 50 °C for 1 h. The reaction mixture was concentrated in vacuo. Water was added and the mixture adjusted to pH 2. 15 The mixture was extracted by CH₂C1₂. The organic phase was passed through a phase separator, then concentrated in vacuo to afford the product. 'H NMR (400 MHz, Methanol-iO S 8.16 (s, IH), 8.06 (d, J - 7.8 Hz, IH), 7.96 (s, IH), 7.73 (d, J = 7.5 Hz, IH), 7.61 (t, J = 7.7 Hz, IH), 7.38 (d, J = 6.9 Hz, IH), 7.30 (d, J = 8.3 Hz, 3H), 7.11 (s, 1 H), 3.18 (h, J = 7.2 Hz, IH), 2.39 (d, J = 1.9 Hz, 3H), 1.16 (d, J = 7.1 Hz, 6H). LCMS m/z 428.31 [M+H]\

303

Compound 12

4-[5-(4-fluoro-3-methyl-phenyl)-6-(methoxymethyl)-!H-pyrrolo[2,3-fJindazol-7-yl]benzoic acid

Step 1. Synthesis of 5-bromo-6-(3-methoxyprop-l-ynyl)-lH-indazole (C3 7)

A solution of 5-bromo-6-iodo-lH-indazole Cl (1 g, 3.1 mmol) in DMF (6.2 mL) was purged with nitrogen. 3-Methoxyprop-l-yne (342 pL, 4.1 mmol), Et₂NH (991 pL, 9.6 mmol), PdCl₂(PPh₃)₂ (HO mg, 0.16 mmol) and Cul (44 mg, 0.23 mmol) were added. The reaction mixture was allowed to heat at 90 °C for 4 h. The mixture was concentrated, then water and 0 CH2CI2 were added. The organic layer was separated by passing through a phase separator. 304

Purification by silica gel chromatography (Eluent: Ethyl acetate/ Hep tan es) afforded the product (540 mg, 66%). ‘H NMR (400 MHz, DMSO-t/Q δ 13.38 (s, IH), 8.17 (s, IH), 8.10 - 8.08 (m, IH), 7.79 (s, 1Η), 4.41 (s, 2H), 3.40 (s, 3H).

Step 2. Synthesis of N-(4-fluoro-3-methyl-phenyl)-6-(3-meth.oxyprop-I-ynyl)-lH~indazol-5-amine (C38)

A solution of 5-bromo-6-(3-methoxyprop-l-ynyl)-lH-indazole C37 (1.6 g, 6.03 mmol), 4-fluoro-3-methyl-aniline (1.1 g, 8.8 mmol), NaOtBu (1.0 g, 10.4 mmol) in tert-butanol (25.9 mL) was purged with nitrogen for 10 min at 40 °C. tBuXPhos Pd G3 (95.8 mg, 0.12 mmol) was added and the mixture was purged with nitrogen for an additional 10 min. The reaction mixture was heated to 70 °C for 1 h. Additional of tBuXPhos Pd G3 (95.8 mg, 0.12 mmol), NaOtBu (1.0 g, 10.4 mmol) and 4-fluoro-3-methyl-aniline (1.1 g, 8.8 mmol) were added and the mixture was stirred overnight. The mixture was cooled and concentrated in vacuo. CH2CI2 and NH4CI were added and the layers were separated and concentrated. The residue was purified b y silica gel chromatography (Gradient: 0 - 100 % EtOAc in heptane) to afford the product (640 mg, 32 %). LCMS m/z 310.2 [M+H]⁺.

Step 3. Synthesis of 5-(4-fhioro-3-methyl-phenyl)-6-(methoxymethyl)-lH-pyrrolo[2,3f]indazole (C39)

A solution of N-(4-fluoro-3-methyl-phenyl)-6-(3-methoxyprop-l-ynyl)-lH-indazol-5amine C38 (590 mg, 1.76 mmol) in DMSO (2.2 mL) was heated at 150 C for 30 min. Water and CH₂CL were added and the organic layer was separated using phase separator. Purified by silica gel chromatography (Gradient: 0-100 % EtOAc in dichloromethane) afforded the product (317 mg, 54 %). ‘H NMR (400 MHz, DMSO-^) δ 12.68 (s, IH), 8.01 (s, IH), 7.63 (s, IH), 7.45 (d, J = 6.9 Hz, IH), 7.40 - 7.31 (m, 3H), 6.71 (s, IH), 4.42 (s, 2H), 3.19 (s, 3H), 2.33 (s, 3H). LCMS m/z 310.3 [M+H]⁺.

Step 4. 1 -[5-(4-jluoro-3-methyl-phenyl)-6-(methoxymethyl)pyrrolo[2,3-f]indazol-l-yl]-2,2dimethyl-propan-l-one (C40)

To a solution of 5-(4-fluoro-3-methyl-phenyl)-6-(methoxymethyl)-lH-pyrrolo[2,3f]indazole C39 (318 mg, 1.03 mmol) in THF (7.1 mL) at 0 °C on an ice bath was added KOtBu (283 pL, 2.3 mmol). 2,2-DimethylpropanoyI chloride (491 pL, 4.0 mmol) was then added dropwise, and the mixture allowed to stir at 0 °C for 1 h. Purification b y silica gel chromatography (Gradient: 0 - 100 % EtOAc in dichloromethane) afforded the product (297 mg, 72 %). ^lH NMR (400 MHz, DMSO-c/₆) δ 8.58 (t, J = 0.9 Hz, IH), 8.43 (d, J = 0.8 Hz, IH), 7.52 (t, J = 0.9 Hz, IH), 7.51 -7.47 (m, IH), 7.41 - 7.39 (m, IH), 7.38 (d, J = 1.4 Hz, IH), 6.906.88 (m, IH), 4.47 (s, 2H), 3.21 (s, 3H), 2.34 (d, J = 1.5 Hz, 3H), 1.52 (s, 9H). LCMS m/z 394.4 [M+H]⁺.

305

Step 5. Synthesis of l-[5-(4-fhioro-3-methyl-phenyl)-7-iodo-6-(methoxymethyl)pyrrolo]2,3f] indazol-1 -yl] -2,2-dimethyl-propan-1 -one (C41) l-iodopyrrolidine-2,5-dione (218 mg, 0.92 mmol) was added portion wise over 30 min to a solution of l-[5-(4-fluoro-3-methyl-phenyl)-6-(methoxymethyl)pyrroIo[2,3-f]indazol-l-yl]2,2-dimethyl-propan-1-one C40 (297 mg, 0.75 mmol) in CH2CI2 (3.1 mL) at 0 °C and the mixture was allowed to stir for 1 h. The reaction mixture was washed with 1M Na2SO₃ and the organic phase was isolated, and passed through a phase separator. Concentration in vacuo afforded the product (350 mg, 80 %). 'H NMR (300 MHz, Methanol-^) δ 8.48 (t, J = 0.8 Hz, IH), 8.23 (d, J = 0.7 Hz, IH), 7.41 (d, J = 0.9 Hz, IH), 7.41 - 7.36 (m, IH), 7.33 - 7.23 (m, 2H), 4.54 (s, 2H), 3.29 (s, 3H), 2.37 (d, J = 2.0 Hz, 3H), 1.58 (s, 9H). LCMS m/z 520.3 [M+H]⁺.

Step 6. Synthesis of 4-[l-(2,2-dimethylpropanoyl)-5-(4-fluoro-3-methyl-phenyl)-6(methoxymethyl)pyrrolo]2,3-f]indazol-7-yl]benzoate (C42)

A mixture of l-[5-(4-fluoro-3-methyl-phenyl)-7-iodo-6-(methoxymethyl)pynOlo[2,3f]indazol-l-yl]-2,2-dimethyl-propan-l-one C41 (50 mg, 0.09 mmol), (4ethoxycarbonylphenyl)boronic acid (36.8 mg, 0.19 mmol) and Pd(dppf)C12 (3.7 mg, 0,005 mmol) in a reaction vial was purged with nitrogen. 1,4-Dioxane (302 pL) and sodium carbonate (147 pL of 2 M, 0.30 mmol) were added and the mixture was allowed to stir at 95 °C for 1 h. Water and CH2CI2 were added, and the phases were separated on a phase separator. Purification by silica gel chromatography (Gradient: 0-100 % CH2CI2 in heptane) to afford the product (35 mg, 67 %). LCMS m/z 542.6 [M+H]⁺.

Step 7. Synthesis of 4-]5-(4-fluoro-3-methyl-phenyl)-6-(methoxymethyl)-lH-pyrrolo[2,3j]indazol-7-yl]benzoic acid (12)

To a solution of ethyl 4-[ l-(2,2-dimethylpropanoyl)-5-(4-fluoro-3-methyl-phenyI)-6(methoxymethyl)pyrrolo[2,3-f]indazol-7-yl]benzoate C42 (35 mg, 0.06 mmol) in THF (778 pL), MeOH (327 pL) was added NaOH (280 pL of 1 M, 0.28 mmol). The mixture was heated at 50 °C for 30 min, then concentrated and re-dissolved in minimal water. The mixture was then acidified by the addition of HCl (280 pL of 1 M, 0.28 mmol), The mixture was filtered and concentrated to afford the product (20.5 mg, 71 %). ’H NMR (400 MHz, DMSO-î/₆) ô 12.97 (s, IH), 12.76 (s, IH), 8.13 (d, J = 7.7 Hz, 2H), 8.09 (s, IH), 7.79 (d, J = 7.7 Hz, 2H), 7,74 (s, IH), 7.56 (d, J = 6.6 Hz, IH), 7.50 - 7,40 (m, 3H), 4.33 (s, 2H), 3.17 (s, 3H), 2.36 (s, 3H). LCMS m/z 430.3 [M+H]\

306

Compound13

4-[5-(2 fluorophenyl)-6-isopropyl~lH-pyrrolo]2,3-f]indazol-7-yl]benzoic acid (13)

NaOtBu

DMSO

C22

Step 1. Synthesis ofN-(2-fluorophenyl)-6-(3-methylbut-l-ynyl)-lH-indazol-5-amine (C43)

Compound C43 was prepared from C22 and 2-fluoro aniline as described for the préparation of C38. Purification by silica gel chromatography (Gradient: 0-30 % EtOAc in Heptane) afforded the product as a gray solid (399 mg, 67%). ’H NMR (400 MHz, Chloroform-d) δ 9.91 (s, IH), 7.96 (s, IH), 7.60 (d, J = 4.3 Hz, 2H), 7.46 (t, J = 8.3 Hz. IH), 7.19 - 7.06 (m, 2H), 6.90 (d, J = 5.9 Hz, IH), 6.53 (s, IH), 2.95 - 2.84 (m, IH), 1.33 (dd, J = 6.9, 1.5 10 Hz, 6H). LCMS m/z 294.3 [M+Hf.

Step 2. Synthesis of 5-(2-fluorophenyl)-6-isopropyl-lH-pyrrolo[2,3f]indazole (C44)

Compound C44 was prepared from C43 using the method described for synthesis of C39 in the préparation of compound 12. Purification by silica gel chromatography (Gradient: 0-40 % EtOAc in heptane) provided the product as a light yellow solid (128.2 mg, 35%). ^lH 15 NMR (400 MHz, Chloroform-d) δ 9.85 (s, IH), 8.04 (s, IH), 7.60 (s, IH), 7.57 - 7.44 (m, 2H), 307

7.42 - 7.33 (m, 2H), 7.21 (s, IH), 6.52 (s, IH), 2.89 (hept, J = 7.9, 7.1 Hz, IH), 1.27 (ddd, J = 11.6, 6.8, 1.8 Hz, 6H). LCMS m/z 294.3 [M+H]⁺.

Step 3. I-[5-(2-fluorophenyl)-6-isopropyl-pyrrolo[2,3-f]indazol-l-yl]-2,2-dimethyl-propan-I-one (C45)

Compound C45 was prepared from C44 as described for the préparation of C40. Purification by silica gel chromatography (Gradient: 0-15 % EtOAc in Heptane) afforded the desired product containing ca. 10 % Piv-OH (by NMR) impurity. The material was used in the subséquent reaction without further purification (114.7 mg, 71%). *H NMR (400 MHz, Chloroform-d) δ 8.69 (s, IH), 8.06 (s, IH), 7.55 (q, J = 7.0 Hz, IH), 7.51 - 7.44 (m, IH), 7.42 7.33 (m, 2H), 7.17 (s, IH), 6.60 (s, IH), 2.89 (dq, J = 12.6, 6.2 Hz, IH), 1.61 (s, 9H), 1.29 - 1.25 (m, 6H). LCMS m/z 378.3 [M+Hf.

Step 4. l-[5-(2-fluorophenyl)-7-iodo-6-isopropyl-pyrrolo[2,3-f]indazol-l-yl]-2,2-dimethylpropari-1-one (C46)

Compound C46 was prepared by treatment of C45 with l-iodopytTolidine-2,5-dione using the method described for the préparation of C41. Silica gel chromatography (Gradient: 010% EtOAc in Heptane) afforded the desired product as a white solid (106.2 mg, 72 %). ’H NMR (400 MHz, Chloroform-d) δ 8.62 (s, IH), 8.07 (s, IH), 7.64 - 7.53 (m, IH), 7.48 - 7.33 (m, 3H), 7.06 (s, IH), 3.14 (dq, J = 14.9, 8.0 Hz, IH), 1.62 (s, 9H), 1.43 (d, J - 7.1 Hz, 3H), 1.36 (d, J = 7.2 Hz, 3H). LCMS m/z 504.3 [M+H]⁺.

Step 5. ethyl 4-[l-(2,2-dimethylpropanoyl)-5-(2-fluorophenyl)-6-isopropyl-pyrrolo[2,3f]indazol- 7-yl]benzoate (C4 7)

Compound C47 was prepared using the method described for préparation of C42. Silica gel chromatography (Gradient: 0-10% EtOAc in heptane) provided the product as a coîorless glassy solid (38.5 mg, 69 %). ‘H NMR (400 MHz, Chloroform-d) δ 8.49 (s, IH), 8.19 (d, J = 7.8 Hz, 2H), 8.07 (s, IH), 7.65 - 7.52 (m, 4H), 7.41 (q, J = 8.9 Hz, 2H), 7.10 (s, IH), 4.47 (q, J = 7.0 Hz, 2H), 3.24 - 3.11 (m, IH), 1.57 (s, 9H), 1.48 (t, J = 7.1 Hz, 3H), 1.17 (dd, J = 19.4, 7.1 Hz, 6H). LCMS m/z 526.5 [M+H]\

Step 6. 4-[5-(2-fluorophenyl)-6-isopropyl-lH-pyrrolo[2,3-flindazol-7-yl]benzoic acid (13)

Compound 13 was prepared by hydrolysis of C47 using a method analogous to that described in the préparation of compound 12. The crude material was dissolved in minimal DMSO and purified by reversed phase chromatography (Cl 8 column: Gradient: 10-100% acetonitrile in water with 0.2 % formic acid modifier) to afford the product as an off-white solid (20.6 mg, 68 %). ^!H NMR (400 MHz, Chloroform-d) δ 8.21 - 8.12 (m, 2H), 7.98 - 7.92 (m, IH), 7.69 - 7.55 (m, 4H), 7.52 - 7.39 (m, 2H), 7.35 (s, IH), 7.04 (d, J = 3.3 Hz, IH), 3.17 (s, IH), 1.23 - 1.09 (m, 6H). LCMS m/z 414.3 [M+H]⁺.

308

Compound14 (E)-8-fluoro-20-isopropyl-11,12-dihydro- 1H-5,18(metheno)dibenzo[5,6:11,12] [1,4]dioxa[7]azacyclododecino[8,9-f] indazole-15-carboxylic acid (14)

ΙΟ

Step 1. Synthesis ofN-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-4-fluoro-phenyl]-6-(3methylbut-l-ynyl)-lH-indazol-5-amine (C48) tBuOH (1000 gL) was added to a vial containing 5-bromo-6-(3-methylbut-l-ynyl)-lHindazole Cl6 (60 mg, 0.2 mmol), 2-[2-[tert-butyl(dimethyl)siIyl]oxyethoxy]-4-fluoro-aniline

309 (98 mg, 0.3 mmol), and NaOtBu (62 mg, 0.6 mmol). The mixture was degassed and purged with N₂ for 10 min at 40 °C. tBuXphos Pd G3 (22 mg, 0.025 mmol) was added and the reaction heated at 40 °C ovemight. The reaction mixture was concentrated in vacuo and purified b y silica gel chromatography (Gradient: 0-40 % EtOAc in heptane) to afford the product as a light yellow solid (51.6 mg, 50 %). ^lH NMR (400 MHz, Chlorofonn-d) δ 7.84 (s, IH), 7.50 (s, IH), 7.39 (s, IH), 7.25 (dd, J = 6.1, 3.9 Hz, IH), 6.71 (dt, J = 10.3, 2.1 Hz, IH), 6.65 - 6.58 (m, IH), 6.41 (s, IH), 4.07 (t, J = 5.7 Hz, 2H), 3.94 (t, J = 5.3 Hz, 2H), 2.82 (dq, J = 13.8, 6.9, 6.3 Hz, IH), 1.26 (dd, J = 6.9, 1.6 Hz, 6H), 0.82 (s, 9H), 0.04 - -0.04 (m, 6H). LCMS m/z 468.46 [M+H]⁺.

Step 2. Synthesis of tert-butyl-[2-[5-fluoro-2-(6-isopropyl-lH-pyrrolo[2,3-f]indazol-5yl)phenoxy]ethoxy] -dimethyl-silane (C49)

A vial containing N-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-4-fluoro-phenyl]-6-(3methylbut-l-ynyl)-lH-indazol-5-amine C48 (85 mg, 0.17 mmol) and Cul (13 mg, 0.07 mmol) were purged with nitrogen. DMF (80 pL) was added and the mixture heated at 80 °C for 30 min. The mixture was purified by reversed phase chromatography (Cl8 g column. Gradient: ΙΟΙ 00% MeCN în water with 0.2% formic acid) to afford the product (62.7 mg, 81 %). ’H NMR (400 MHz, DMSO-î/₆) δ 13.10 - 12.67 (m, IH), 8.25 (s, IH), 7.72 (s, IH), 7.70 - 7.62 (m, IH), 7.54 - 7.47 (m, IH), 7.26 - 7.18 (m, 2H), 6.63 (s, IH), 4.37 - 4.19 (m, 2H), 3.91 - 3.79 (m, 2H), 3.02 - 2.91 (m, IH), 1.41 (ddd, J = 16.9, 6.9, 1.8 Hz, 6H), 0.88 (s, 9H), 0.00 (s, 3H), -0.09 (s, 3H). LCMS m/z 468.4 [M+H]⁺.

Step 3. 1 -[5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-4-fluoro-phenyl]-6-isopropylpyrrolof2,3-]] indazol-l-yl]-2,2-dimethyl-propan-l-one (C50)

To a solution of tert-butyl-[2-[5-fluoro-2-(6-isopropyl-lH-pyrrolo[2,3-f|indazol-5yl)phenoxy] ethoxy]-dimethyl-silane C49 (165 mg, 0.35 mmol) în THF (5 mL) at 0 °C was added KOtBu (74 mg, 0.66 mmol), and the mixture was allowed to stir for 5 min. 2,2dimethylpropanoyl chloride (170 pL, 1.4 mmol) was added and the reaction was stirred 0 °C for I h. The reaction mixture was then concentrated in vacuo. Silica gel chromatography (Gradient: 0-10 % EtOAc în heptane) afforded the product as a pale yellow oil (139.3 mg, 71 %). LCMS m/z 552.31 [M+H]⁺.

Step 4. l-[5-[2-[2-[tert-butyl(dimethyl)silyl] oxyethoxy]-4-fluoro-phenyl]-7-iodo-6-isopropylpyrrolo[2,3-f] indazol-1-yl]-2,2-dimethyl-propan-l-one (C51)

N-iodosuccinimide (64 mg, 0.28 mmol) was added to a solution of l-[5-[2-[2-[tertbutyl(dimethyl)silyl]oxyethoxy]-4-fluoro-phenyl]-6-isopropyl-pyrrolo[2,3-f] indazol-l-yI]-2,2dimethyl-propan-l-one C50 (135 mg, 0.24 mmol) in CH2CI2 (2 mL) and the reaction was stirred at room température for 30 min. The mixture was concentrated in vacuo, and the crude product purified by silica gel column chromatography (Gradient; 0-5 % EtOAc in Heptane) to afford the 310 product as a bright yellow fluorescent viscous oil (119.2 mg, 70%). ’H NMR (400 MHz, Chloroform-d) δ 8.55 (s, IH), 8.02 (s, IH), 7.25 - 7.22 (m, IH), 6.97 (s, IH), 6.91 (d, J = 10.1 Hz, IH), 6.83 (t, J = 7.8 Hz, IH), 3.93 (t, J = 4.8 Hz, 2H), 3.62 (t, J = 4.9 Hz, 2H), 3.13 - 3.00 (m, IH), 1.59 (s, 9H), 1.38 (d, J = 6.9 Hz, 3H), 1.28 (d, J = 7.2 Hz, 3H), 0.65 (s, 9H), -0.23 (s, 5 3H), -0.38 (s, 3H). LCMS m/z 678.3 [M+H]⁺.

Step 5. Synthesis of methyl 3-[tert-butyl(dimethyl)silyl]oxy-4-[5-[2-[2-[tertbutyl(dimethyl)silyl] oxyethoxy]-4-fluoro-phenyl]-1 -(2,2-dimethylpropanoyl)-6-isopropylpyrrolo[2,3-f]indazol- 7-yl] benzoate (C52)

THF (6 mL) and water (1.6 mL) were added to a vial containing a mixture of 1 -[5-[2-[210 [tert-buÎyl(dimethyl)silyl]oxyethoxy]-4-fluoro-phenyI]-7-iodo-6-isopropyl-pynOlo[2,3-f]indazoll-yI]-2,2-dimethyl-propan-l-one C51 (100 mg, 0.14 mmol), methyl 3-[tertbutyl(dimethyl)silyl]oxy-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)benzoate (107 mg, 0.27 mmol), and K3PO4 (102 mg, 0.48 mmol). The mixture was purged with nitrogen, then SPhos (16 mg, 0.04 mmol) and Pd2(dba)₃ (14 mg, 0.015 mmol) were added and the mixture heated to 60 °C 15 for 3 days. The reaction mixture was partîtioned between water (10 mL) and dichloromethane (10 mL). The mixture was then passed through a phase separator to collect the organic phase and the solvent was evaporated in vacuo. The mixture was purified by silica gel chromatography (Gradient: 0-20 % EtOAc in heptane) to afford two products.

Product 1 (Two TBS groups remain intact). Methyl 3-[tert-butyl(dimethyl)silyI]oxy-420 [5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-4-fluoro-phenyl]-l-(2,2-dimethylpropanoyl)-6isopropyl-pyrrolo[2,3-f]indazol-7-yl]benzoate (17.1 mg, 11%). ’H NMR (300 MHz, Chloroform-d) δ 8.25 (dt, J = 18.1, 0.9 Hz, IH), 8.01 (dd, J = 2.7, 0.8 Hz, IH), 7.48 (dt, J = 7.6, 2.2 Hz, IH), 7.37 - 7.29 (m, 2H), 7.29 - 7.19 (m, IH), 7.03 - 6.34 (m, 3H), 4.10 - 3.93 (m, 5H), 3.76 - 3.62 (m, 2H), 3.09 - 2.86 (m, IH), 1.54 (s, 9H), 1.16-1.02 (m, 6H), 0.87 - 0.53 (m, 18H), 25 0.07 - -0.37 (m, 12H). LCMS m/z 816.48 [M+H]⁺. The NMR spectrum revealed that dba was present as an impurity

Product 2 (mono-cfes-TBS C52). The product mono-i/e^-TBS was obtained as a light yellow viscous oil. Methyl 4-[5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-4-fluoro-phenyI]-l(2,2-dimethyIpropanoyl)-6-isopropyl-pyrrolo[2,3-f|indazol-7-yl]-3-hydroxy-benzoate (77.8 mg, 30 51 %). 'H NMR (400 MHz, Chloroform-d) δ 8.24 (s, IH), 8.03 (s, IH), 7.75 - 7.67 (m, 2H),

7.43 - 7.35 (m, 2H), 7.09 (d, J = 6.9 Hz, IH), 6.97 - 6.85 (m, 2H), 5.33 - 5.16 (m, IH), 4.02 3.95 (m, 5H), 3.72 - 3.63 (m, 2H), 3.03 - 2.81 (m, IH), 1.53 (s, 9H), 1.07 (ddd, J = 22.1, 10.7, 7.1 Hz, 6H), 0.70 - 0.61 (m, 9H), -0.18 -0.38 (m, 6H). LCMS m/z 699.78 [M+H]⁺. The NMR spectrum revealed that the reduced, deprotected boronate was present as an impurity.

311

Step 6. 4-]1 -(2,2-dimethylpropanoy 1)-5-(4-fiuoro-2-(2-hydroxyethoxy)phenyl]-6-isopropylpyrrolo(2,3-f]indazol- 7-yl]-3-hydroxy-benzoate (C53)

To a solution of methyl 4-[5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-4-fluorophenyl]-l-(2,2-dimethylpropanoyl)-6-isopropyl-pyrrolo[2,3-f]mdazol-7-yI]-3-hydroxy-benzoate C52 (75 mg, 0.07 mmol) in THF (2 mL) was added TB AF (75 pL of 1 M, 0.08 mmol) and the reaction stirred at room température ovemight, The reaction mixture was partitioned between water (5 mL) and dichloromethane (5 mL), and passed through a phase separator. The organic phase was collected and the solvent was evaporated in vacuo. The product mixture was purified by silica gel chromatography (Gradient: 0-60 % EtOAc in Heptane) to afford the product as a white solid (29.7 mg, 72 %). 'H NMR (300 MHz, Chloroform-d) δ 8.30 - 8.23 (m, IH), 8.04 7.92 (m, IH), 7.74 - 7.66 (m, 2H), 7.56 - 7.41 (m, IH), 7.40 - 7.34 (m, IH), 7.13 - 7.09 (m, IH), 7.00 - 6.83 (m, 2H), 6.12 (s, IH), 5.25 (s, IH), 4.04 - 3.79 (m, 5H), 3.68 - 3.33 (m, 2H), 3.00 2.77 (m, 1 H), 1.53 (s, 9H), 1.07 (ddd, J = 14.6, 7.1, 3.8 Hz, 6H). LCMS m/z 588.3 [M+H]~ Step 7. Synthesis methyl (E)-8-fluoro-20-isopropyl-l-pivaloyl-ll,12-dihydro-lH-5_f18(methenσ)dibenzo(5,6:11,12] (1,4] dioxa(7] azacyclododecino(8,9-fj indazole-15-carboxylate (C54)

To a solution of methyl 4-[l-(2,2-dimethylpiOpanoyl)-5-[4-fluoro-2-(2hydroxyethoxy)ph en yl]-6-isopropyl-pyrrolo [2,3-f]indazol-7-yI]-3-hydroxy-benzoate (18 mg, 0.03 mmol) in toluene (30 mL) under a nitrogen atmosphère was added 2-(tributyI-À⁵phosphaneylidene)acetonitrile (480 pL, 1.83 mmol). The reaction mixture was heated to 100 °C ovemight. The solvent was evaporated in vacuo and the mixture was purified by silica gel chromatography (Gradient: 0-10 % EtOAc in heptane) to afford the product C54 as a white solid (2.2 mg, 12 %). 'H NMR (400 MHz, Chloroform-d) δ 8.33 (s, IH), 8.06 - 8.01 (m, 2H), 7.88 7.77 (m, 3H), 7.30 - 7.27 (m, IH), 6.90 (td, J = 8.5, 2.7 Hz, IH), 6.49 (dd, J = 9.3, 2.7 Hz, IH), 4.16-4.10 (m, 1H),3.97 (s, 3H), 3.88 (d, J = 9.7 Hz, 2H), 3.18 (dd, J = 11.0, 8.0 Hz, IH), 2.88 2.73 (m, IH), 1.56 (s, 9H), 1.09 (d, J = 6.8 Hz, 3H), 0.88 - 0.83 (m, 3H). LCMS m/z 570.31 [M+H]⁺.

Step 8. Synthesis of (E)-8-fluoro-20-isopropyl-l 1,12-dihydro-1H-5,18(metheno)dibenzo[5,6:11,12]]1,4]dioxa(7]azacyclododecino[8,9-f] indazole-15-carboxvlic acid (14)

NaOH (21 pL of 1 M, 0.021 mmol) was added to a solution of methyl 22-(2,2dimethylpropanoyl)-5-fluoro-28-(propan-2-yl)-8,11 -dioxa-1,22,23triazahexacyclo[ 16.9.1.02,7.012,17.019,27.021,25]octacosa2(7),3,5,12,14,16,18(28),19,2I(25),23,26-undecaene-14-carboxylate C54 (2 mg, 0.004 mmol) in THF (40 pL) and MeOH (20 pL). The reaction mixture was heated to 50 °C for 50 min. The 312 solvent was evaporated in vacuo and HCl (21 pL of l M, 0.021 mmol) was added. A white precipitate formed and the solvent was evaporated in vacuo. The product mixture was dissolved in minimal DMSO, and purified by reverse phase chromatography (Cl 8 column. Gradient: ΙΟΙ 00 % MeCN in water with 0.2 % formic acid) to afford the desired product as a white solid (1.3 5 mg, 78 %). ’H NMR (400 MHz, Méthanol-^) δ 8.19 (s, IH), 8.04 (d, J = 7.8 Hz, IH), 7.94 (s, IH), 7.86 - 7.79 (m, 2H), 7.26 (s, IH), 7.22 (s, IH), 6.94 (td, J = 8.8, 4.6 Hz, IH), 6.75 - 6.68 (m, IH), 4.18 (d, J = 11.0 Hz, IH), 3.98 -3.86 (m, 2H), 3.15 (t, J = 9.7 Hz, IH), 2.84- 2.72 (m, IH), 1.11 (dd, J = 6.9, 1.5 Hz, 3H), 0.89 (dd, J = 7.2, 1.6 Hz, 3H). LCMS m/z 472.2 [M+H]\

Compound 15, 16 and 17

2,2,2-trifluoro-î-[4-[5-(4-]luorophenyl)-6-tetrahydropyran-4-yl-IH-pyrrolo[2,3-f] indazol- 7yl]phenyl]éthanol (15), 2,2,2-tri]hioro-l-[4-[5-(4-Jluorophenyl)-6-tetrahydropyran~4-yl-lHpy rrolo [2,3-f] indazol-7-yl]phenyl] éthanol (16) ENANT-1 and 2,2,2-trifluoro-l-[4-[5-(4fluorophen.yl)-6-tetrahydropyran-4-yl-l H-pyrrolo[2,3-f] indazol- 7-yl]phenyl] éthanol (17)

ENANT-2

Step 1. Synthesis of l-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-7-[4-(2,2,2-trifluoro-lhydroxy-ethyl)phenyl]pyrrolo[2,3-f] indazol- 1-yl]-2,2-dimethyl-propan-I-one (C55)

313

A solution of Na₂CO₃ (225 pL of 2 M, 0.45 mmol) was added to a solution of 1-(5-(4fluoroρhenyl)-7-iodo-6-tetrahydropyran-4-yl-pyrrolo[2,3-f]indazol-l-yl]-2,2-dimethyl·propan-lone (100 mg, 0.18 mmol) S4, 2,2,2-trifluoro-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl] éthanol (66 mg, 0.22 mmol) and Pd(PPh₃)₄ (10 mg, 0.009 mmol) in 1,4-dioxane (750 pL) and DMF (750 pL). The reaction was heated at 150 °C for 30 min. Water and CH₂C1₂ were added and the mixture was extracted with CH₂C1₂ (x 3). The organic phases were filtered through a phase separator, combined and concentrated in vacuo to afford the product which was used in the subséquent step without further purification. LCMS m/z 594.4 [M+H] \

Step 2. Synthesis of 2,2.2-trifluoro-l-[4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lHpyrrolo]2,3-f]indazol-7-yl]phenyl]éthanol (15)

NaOH (36 mg, 0.9 mmol) was added to a solution of C55 in THF (750 pL) and water (250 pL). The reaction was heated at 50 °C for 40 h. The pH of the mixture was adjusted to pH 7 by the addition of 1 M HCl. The mixture was extracted with CHC1₃: IP A (3:1) (x 3). The organic phases were filtered through a phase separator, combined and evaporated in vacuo. The crude was dissolved in DMSO and purified by reversed-phase HPLC (Method: C18 Waters Sunfire column (30 xl50 mm, 5 micron). Gradient: 10-100 % MeCN in H₂O with 0.2 % formic acid) to afford the product as a white solid.

Step 3. Préparation of2,2,2-trifluoro-1-]4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lHpyrrolo[2,3-f]indazol-7-yl]phenyl]éthanol (16) and 2,2,2-trifluoro-l-]4-[5-(4-fluorophenyl)-6tetrahydropyran-4-yl-lH-pyrrolo[2,3-f] indazol- 7-yl]phenyl]éthanol (17)

Racemic compound 2,2,2-trifluoro-l-[4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-l Hpyrrolo[2,3-f]indazol-7-yl]phenyl]ethanol 15 (30 mg, 0.06 mmol) was separated into its constituent enantiomers by chiral SFC séparation. Column: Daicel Chiralpak IB, 10 x 250 mm. Mobile phase: 20 % MeOH (5 mM ammonia), 80 % CO₂. Flow: 15 mL/min. Two products were obtained. Compound 16 was the first elutîng enantiomer and compound 17 was the second eluting enantiomer.

2,2,2-trifluoro- l-[4-[5-(4-fl uorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3f]îndazol-7-yl]phenyl]éthanol (16) ENANT-l (10.1 mg, 61 %). ’H NMR (300 MHz, Methanold₄) δ S.34 (s, IH), 7.68 (d, J = 8.0 Hz, 2H), 7.55 (dt, J = 8.9, 2.7 Hz, 4H), 7.42 (t, J = 8.6 Hz, 2H), 7.34 (t, J = 1.1 Hz, IH), 7.26 (d, J = 1.2 Hz, IH), 5.16 (q, J = 7.3 Hz, IH), 3.79 (dd, J = 11.4,4.1 Hz, 2H), 3.20 (t, J = 11.4 Hz, 2H), 3.11 - 3.02 (m, IH), 1.88 - 1.74 (m, 2H), 1.69 (d, J = 13.1 Hz, 2H). LCMS m/z 510.2 [M+Hf.

2,2,2-trifluoro-l-[4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-I H-pyrrolo[2,3f]indazol-7-yl] phenyl] éthanol (17) ENANT-2 (12.1 mg, 74%). 'H NMR (300 MHz, Methanold₄) δ 8.41 (s, 1Η), 7.68 (d, J = 8.0 Hz, 2H), 7.59 - 7.50 (m, 4Η), 7.43 (t, J = 8.6 Hz, 2H), 7.35 (d, 314

J = 1.2 Hz, IH), 7.28 (d, J = 1.2 Hz, IH), 5.17 (q, J = 7.1 Hz, IH), 3.86 - 3.73 (m, 2H), 3.19 (m, J = 11.5 Hz, 2H), 3.06 (m, IH), 1.88 - 1.74 (m, 2H), 1.69 (d, J = 12.8 Hz, 2H). LCMS m/z 510.2 [M+Hf.

Compound 18

5-(4-fluorophenyl)-7-(4-pyridyl)-6-tetrahydropyran~4-yl-lH-pyrrolo[2,3-fJindazole (18)

Step 1. l-[5-(4-fluorophenyl)-7-(4-pyridyl)-6-tetrahydropyran-4-yl-pyrrolo[2,3-fjindazol-l-yl]2,2-dimethyl-propan-1 -one (C56)

1,4-Dîoxane (750 pL) and DMF (750 pL) were added to a vial containing 1-(5-(4fluorophenyl)-7-iodo-6-tetrahydropyran-4-yl-pynOlo(2,3-f]indazol-l-yl]-2,2-dimethyl-propan-lone S4 (100 mg, 0.18 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-y])pyridine (45 mg, 0.22 mmol), and Pd(PPhj)4 (10 mg, 0.009 mmol) under a nitrogen atmosphère. A solution of NaaCOj (225 pL of 2 M, 0.45 mmol) was then added and the reaction was heated at 100 °C for 7

h. Water and CH₂C1₂ were added, and the mixture was extracted with CH2CI2 (x 3). The organic phases were filtered through a phase separator, and concentrated in vacuo to afford the product which was used without further purification. LCMS m/z 497.2 [M+H]⁺.

315

Step 2. Synthesis of 5-(4fhiorophenyl)-7-(4-pyridy')-6-tetrahydropyran-4-yl-IH-pyrrolo[2,3fjindazole (18)

KO H (30 mg, 0.5 mmol) was added to a solution of l-[5-(4-fluorophenyl)-7-(4-pyridyl)6-tetrahydropyran-4-yl-pyrrolo[2,3-f]indazol-l-yI]-2,2-dimethyl-propan-l-one C56 in EtOH (750 pL) and Water (250 pL). The reaction mixture was heated at 50 °C for 72 h. The pH of the reaction mixture was adjusted to the pH to 7 with 1M HCl, The mixture was then extracted with CHCfi: IPA (3:1) (x 3). The organic phases were filtered through a phase separator, combined and concentrated in vacuo. Purification by reversed-phase HPLC (Method: Cl8 Waters Sunfire column (30 xl50 mm, 5 micron). Gradient: 10-100 % MeCN in H₂O with 0.2 % formic acid) afforded the product as a white solid (22.6 mg, 29 %). *H NMR (400 MHz, DMSO-î/₆) δ 12.63 (s, IH), 8.87 - 8.63 (m, 2H), S.01 (d, J = LO Hz, IH), 7.68 - 7.60 (m, 2H), 7.60 - 7.55 (m, 2H), 7.56 - 7.48 (m, 2H), 7.34 (t, J = 1.1 Hz, IH), 7.08 (d, J = 1.1 Hz, IH), 3.74 (d, J = 11.4 Hz, 2H), 3.20 - 3.10 (m,2H), 3.04 (m, IH), 1.69 (m,4H). LCMS m/z 413.1 [M+H]⁺.

Compounds 19-32

Compounds 19-32 were prepared in two steps from S4 according to the method described for the préparation of compound 18 (Suzuki coupling, pivaloyl group deprotection). In some examples, an alternative cataiyst is used in the Suzuki coupling step, as noted in the table footnotes.

Table 4. Method ofpréparation, structure, physicochemical data for compounds 19-32

Compound	Method/Product	Boronic acid or ester	'H NMR; LCMS m/z [M+H]’
	Compound 18l from S4 CN A H	CN	‘H NMR (400 MHz, DMSOd6) δ 12.62 (s, IH), 8.07 7.98 (m, 3H), 7.79 - 7.70 (m, 2H), 7.67 - 7.60 (m, 2H), 7.56
	N-	'xÿP' / \		-7.48 (m, 2H), 7.27 (t, J = 1.1
19	V	X L /—( p P F	HO OH	Hz, IH), 7.08 (t, J = 0.9 Hz, IH), 3.73 (d, J = 10.4 Hz, 2H), 3.19-3.06 (m, 2H), 3.07 - 2.95 (m, IH), 1.64 (m, 4H). LCMS m/z 436.98 [M+H] \

316

Compound	Method/Product	Boronic acid or ester	‘H NMR; LCMS m/z [M+H]
20	Compound 18! from S4 NHMe OA Ao O H f^ L £ Va p fl F	S02NHMe fl HO OH	’H NMR (400 MHz, DMSOd6fô 12.59 (brs, IH), 8.01 (t, J= 1.3 Hz, IH), 7.98-7.91 (m, 2H), 7.79 - 7.71 (m, 2H), 7.67 - 7.59 (m, 2H), 7.59 7.48 (m, 3H), 7.26 (t, J= 1.1 Hz, IH), 7.08 (tbr s, IH), 3.73 (d, J =11.2 Hz, 2H), 3.18-3.06 (m, 2H), 3.072.95 (m, 1 H), 2.53 (d, J = 5.0 Hz, 3H), 1.67 (m, 4H). LCMS m/z 505.2 [M+Hf.
21	Compound 181 from S4 p-O (j H N-AaV /A n. JL L H p ^-^aa-n \—/ fl F	SOoMe fl ,BS O 0	’H NMR (400 MHz, DMSOdj 6 12.81 - 12.42 (m, IH), 8.15-8.06 (m, 2H), 8.01 (t, J = 1.3 Hz, IH), 7.84 - 7.75 (m, 2H), 7.68 - 7.59 (m, 2H), 7.57 -7.48 (m, 2H), 7.28 (t, J =1.1 Hz, 1 H), 7.08 (t, J = 0.9 Hz, 1 H), 3.80 - 3.68 (m, 2H), 3.35 (s, 3H), 3.13 (td, J = 11.3,4.8 Hz, 2H), 3.08 -2.97 (m, IH), 1.75 - 1.58 (m, 4H). LCMS m/z 490.1 [M+H]’.
22	Compound 181 from S4 OH O H 'i n>aV aa a JL Γ /—( p fl F	OH .A HO OH	’H NMR (400 MHz, DMSO4/)6 12.54 (s, IH), 9.53 (s, IH), 7.97 (mz, IH), 7.61 7.55 (m, 2H), 7.52 - 7.45 (m, 2H), 7.31 -7.23 (m, 2H), 7.16 (m, IH), 7.05 (m, IH), 6.96 6.89 (m, 2H), 3.72 (d, J = 10.3 Hz, 2H), 3.08 (t, J = 11.1 Hz, 2H), 2.98 -2.83 (m, IH), 1.77 - 1.54 (m,4H). LCMS m/z 428.2 [M+Hf.
23	Compound 18~ from S4	HO. ^OH Q A HO OH	’H NMR (400 MHz, DMSOd6) δ 12.56 (d, J = 1.4 Hz, lH),8.14(s, 2H), 7.99 (t, J = 1.3 Hz, IH), 7.97-7.91 (m, 2H), 7.65 -7.58 (m, 2H), 7.55 -7.44 (m, 4H), 7.21 (t, J = 1.1 Hz, IH), 7.06 (t, J = 0.9 Hz, IH), 3.72 (d,J=10.7 Hz, 2H), 3.14-3.04 (m, 2H), 3.03 -2.93 (m, IH), 1.74-1.60 (m, 4H). LCMS m/z 456.2

317

Compound	Method/Product	Boronic acid or ester	’H NMR; LCMS m/z [M+H]+
	HO. BOH O H \ 4 L l[ >4 P ô F		[M+H]+.
24	Compound 183 from S4 Fr PH FS H < L if ?—( p N x---7 Q F	OH F3C^F] HO OH	'H NMR (400 MHz, DMSOd6) δ 12.56 (s, IH), 10.76 (s, IH), 7.99 (s, IH), 7.65 - 7.54 (m, 4H), 7.50 (t, J = 8.7 Hz. 2H), 7.22 (d, J =8.2 Hz, IH), 7.16 (t, J= 1.2 Hz, IH), 7.08 (d, J= 1.1 Hz, 1 H), 3.74 (d, J = 10.9 Hz, 2H), 3.19-3.02 (m, 2H), 2.98 -2.80 (m, IH), 1.65 (m, 4H). LCMS m/z 496.2 [M+H]+.
25	Compound 183 from S4 >N'NH N । y^N F4 H < JL L / \ p N —' f F	N-NH 9 ho'%h	'H NMR (400 MHz, DMSOd^d 12.60 (s, IH), 8.268.16 (m, 2H),8.01 (s, IH), 7.79-7.71 (m, 2H), 7.68 7.60 (m, 2H), 7.57- 7.47 (m, 2H), 7.29 (t, J= 1.2 Hz, IH), 7.09(d, J= 1.0 Hz, 1 H), 3.74 (d,J= 11.3 Hz, 2H), 3.183.08 (m, 2H), 3.03 (p, J = 8.6, 8.0 Hz, IH), 1.77 - 1.63 (m, 4H). LCMS m/z 480.5 [M+H]4.
26	Compound 181 from S4 H ,-N ~ F F° H Γ /—\ Nx L £ >—( p À F	&-Q· O	‘H NMR (400 MHz, Methanol-d4) δ 8.05 (d, J = 1.0 Hz, IH), 7.75 - 7.66 (m, IH), 7.58 - 7.49 (m, 3H), 7.47 -7.37(m, 2H), 7.14 (d, J = 1.1 Hz, IH),6.82-6.75 (m, 2H), 3.97 -3.76 (m, 2H), 3.29 (m, 2H, behind solvent peak), 3.19 (tt, J = 12.3,3.4 Hz, IH), 1.91 (qd, J =12.5, 4.3 Hz, 2H), 1.73 (d, J= 12.7 Hz, 2H). LCMS m/z 429.2

318

Compound	Method/Product	Boronic acid or ester	Ή NMR; LCMS m/z [M±H]+
			[M+H]'.
27	From compound 244 O 11 OH H0\/ O H n' L Γ Va p \—/ 0 F		‘11 NMR (400 MHz, DMSOdf) δ 12.56 (s, IH), 11.37 (s, 1 H), 7.99 (s, IH), 7.88 (d, J = 2.3 Hz, 1 H), 7.65 -7.59 (m. 3H), 7.54- 7.46 (m, 2H), 7.18 (t, J= 1.1 Hz, IH), 7.14 (d, J = 8.4 Hz, IH), 7.08 (d, J= 1.1 Hz, IH), 3.73 (d,J=ll.lHz, 2H), 3.09 (dd, J = 14.1, 11.4 Hz, 2H), 2.91 (h, J = 7.8 Hz, IH), 1.72- 1.55 (m, 4H). LCMS m/z 472.2 [M+H]“.
28	Compound 18' from S4 VV°H H L/ Nw JL L /—( P Q F	P-Q o ΞΕ	‘H NMR (400 MHz, DMSOd6)S 12.55 (d, J = 1.4 Hz, IH), 9.54 (s, IH), 7.98 (t, J = 1.3 Hz, IH), 7.64 - 7.57 (m, 2H), 7.54 - 7.46 (m, 2H), 7.36 - 7.29 (m, IH), 7.23 (t, J= 1.1 Hz, IH), 7.05 (m, IH), 6.91 (m, 2H), 6.84-6.79 (m, IH), 3.74 (dd, J = 11.3, 3.9 Hz, 2H), 3.10 (t, J = 11.3 Hz, 2H), 3.03 -2.90 (m, IH), 1.72 (qd, J= 12.4,4.2 Hz, 2H), 1.63 (d, J =12.7 Hz, 2H). LCMS m/z 428.2 [M+H]’.
29	Compound 18’ from S4 F OH F H / NJ JL L /—( ° ^A/A J—/ 0 F	OH ιΓΎ hoboh	’H NMR (400 MHz, DMSO4S) δ 12.58 (d, J = 1.4 Hz, IH), 10.35 (s, IH), 7.99 (m, IH), 7.58 (m, 2H), 7.54-7.46 (m, 2H), 7.22 (t, J = 1.1 Hz, IH), 7.18-7.08 (m, 2H), 7.07 (m, 1 H), 3.82 - 3.66 (m, 2H), 3.17-3.02 (m, 2H), 2.93 (h, J = 8.2 Hz, IH), 1.65 (m, 4H). LCMS m/z 464.2 [M+H]\

319

Compound	Method/Product	Boronic acid or ester	‘H NMR; LCMS m/z [M+H] ’
30	Compound I81 from S4 HO / O H Γ n. L Γ J—( p 0 F	T	Ή NMR (400 MHz, DMSOd5) δ 12.51 (d, J= 1.5 Hz, IH), 7.98 (t, J= 1.3 Hz, IH), 7.68 -7.57 (m, 4H), 7.55 7.46 (m, 2H), 7.46 - 7.40 (m, 2H), 7.20 (t, J= 1.1 Hz, IH), 7.05 (d, J = 0.9 Hz, IH), 5.10 (s, IH), 3.73 (d, J = 10.9 Hz, 214),3.16-3.03 (m, 2H), 3.03 -2.91 (m, IH), 1.69 (m, 4H), 1.53 (s, 6H). LCMS m/z 470.2 [M+H] 4
31	Compound 18‘ from S4 ox Z-OH MeO^x^f H / /—\ Z L I ΖΖ P N 5—/ Φ F	O^O Me MeoXy T. J3	'H NMR (400 MHz, DMSOdb) δ 13.08 (s, IH), 12.52 (s, IH), 7.98 (s, IH), 7.72-7.68 (m, 2H), 7.67-7.55 (m, 2H), 7.54- 7.45 (m, 3H), 7.08 (s, 114),6.98 (s, IH), 3.80 (s, 3H), 3.70 (t, J = 11.0 Hz, 2H), 3.07 (t, J = 11.6 Hz, 2H), 2.90 - 2.80 (m, IH), 1.71 - 1.48 (m,4H). LCMS m/z 486.42 [M+Hf.
32	from S4 See footnote5 Ct y-OH θΑν H / n . L L /—\ ° e? F	Φ \__// Y)—m o o	'H NMR (400 MHz, DMSOJ6)Ô 13.10 (s, IH), 12.59 (s, IH), 8.00 (s, IH), 7.93 (d, J = 7.5 Hz, IH), 7.81 (d, J = 7.5 Hz, IH), 7.70-7.63 (m, IH), 7.62- 7.57 (m, IH), 7.557.47 (m, 2H), 7.08 (d, J = 2.7 Hz, 2H), 5.29 (p, J = 8.7 Hz, IH), 3.73 (t,J=11.7Hz, 2H), 3.10 (t, J = 11.3 Hz, 2H), 2.92 (t, J = 13.2 Hz, IH), 2.452.36 (m, 2H), 2.00 - 1.90 (m, 2H), 1.73 - 1.53 (m, 6H). LCMS m/z 527.2 [M+H]+.

'* Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 xl50 mm, 5 micron). Gradient: 10-100 % MeCN in H₂O with 0.2 % formic acid.

²· Suzuki coupling reactions with Pd(dppf)CÎ₂ and Na₂CO3 in 1,4-dioxane at 90 °C.

Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 xl50 mm, 5 5 micron). Gradient: 10-100 % MeCN in H₂O with ammonium formate.

³‘ Purification by reversed-phase HPLC. Method: Cl 8 Waters Sunfire column (30 xl 50 mm, 5 micron). Gradient: 10-100 % MeCN in H₂O with 0.1 % TFA.

320

Compound 27 was obiained as an additional product of reaction in préparation of compound 24. Purification by reversed-phase HPLC. Method: Cl 8 Waters Sunfire column (30 xl50 mm, 5 micron). Gradient: I0-100 % MeCN in H₂O with O.l % TFA.

⁵‘ Suzuki coupling conditions: Pd(OAc)₂, XPhos, K3PO4, 1,4-dioxane 90 °C. Hydrolysis:

NaOH

Compound 33

4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3-f]indazol-7-yl]benzoic acid (33)

321

Préparation of 4-]5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrrolo[2,3-f] indazol- 7yl]benzoic acid (33) from S6

Step 1. Synthesis of ethyl 4-[l-(benzenesulfonyl)-5-(4-fluorophenyl)-6-tetrahydropyran-4-ylpyrrolo[2,3-f]indazol-7-yl]benzoate (C57)

A mixture of l-(benzenesulfonyl)-5-(4-fluorophenyl)-7-iodo-6-tetrahydropyran-4-ylpyrrolo[2,3-f]indazole S6 (103.8 g, 172.6 mmol), (4-ethoxycarbonylphenyl)boronic acid (67 g, 345.4 mmol), Pd(dppf)Cl₂ (6.4 g, 7.8 mmol) and Na₂CO₃ (270 mL of 2 M, 540 mmol) in 1,4dioxane (1 L) was purged with nitrogen for 20 min, then heated at 90 °C for 1 h. The mixture was filtered through Celite®, washing with EtOAc (500 mL). The fïltrate was concentrated to dryness in vacuo. EtOAc (1 L) and water (300 mL) were added. The organic layer was separated and filtered through Celite®. The organic layer was then washed with 1 M NaOH (300 mL x 2), and brine. The organic layer was dried, and concentrated in vacuo. The residue was dissolved in CH₂C1₂ (200 mL) and the solution was purified by silica gel chromatography. (Column: 3 kg Silica gel. Gradient: 0-100 % EtOAc in heptane) to afford the product as a white, foamy solid (-102 g). TBME (550 mL) was added, and the suspension was allowed to stir at room température for 1 h. The solid was filtered (washing with 200 mL MTBE). CH2CI2 (300 mL) and EtOAc (400 mL) were added to afford a clear solution which was treated with MP-TMT Pd resin (45 g) and allowed to stir ovemight, The suspension was filtered, and the fïltrate concentrated in vacuo to afford the product as a white solid (96 g, 89 %). ^lH NMR (300 MHz, Chloroform-d) δ 8.33 - 8.22 (m, 2H), 8.15 (d, J = 0.8 Hz, IH), 8.10 (t, J = 0.9 Hz, IH), 7.91 (dd, J = 8.4, 1,3 Hz, 2H), 7.65 - 7.56 (m, 2H), 7.56 - 7.46 (m, IH), 7.46 - 7.35 (m, 4H), 7.35 - 7.23 (m, 2H), 7.06 (d, J = 1.0 Hz, IH), 4.49 (q, J = 7.1 Hz, 2H), 3.86 (dd, J = 1 L4, 3.5 Hz, 2H), 3.22 (t, J = 11.0 Hz, 2H), 3.05 (ddd, J = 12.2, 8.9,3,3 Hz, IH), 1.83 (qd, J = 12.6, 4.3 Hz, 2H), 1.64 (s, 2H), 1.49 (t, J = 7.1 Hz, 3H). LCMS m/z 624.3 [M+H]L

Step 2. 4-]5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo]2,3-f]indazol- 7-yl]benzoic acid (33)

Piperidine (54 mL, 546.0 mmol) and NaOH (1350 mL of 1 M, 1.350 mol) were added to a solution of ethyl 4-[l-(benzenesulfonyl)-5-(4-fluorophenyl)-6-tetrahydropyran-4-ylpyrrolo[2,3-f]indazol-7-yl]benzoate C57 (170 g, 272.6 mmol) in THF (1800 mL) and MeOH (1800 mL) and the mixture was heated to 50 °C for 3.5 h. Upon cooling, HCl (700 mL of 2 M, 1.40 mol) was added to adjust the mixture to pH = 2. The solvent volume was reduced (by - 3 L) by concentration in vacuo. The light yellow precipitate was filtered off, washing the filter cake with water (x 3), TBME (250 mL x 2) and EtOAc (250 mL x 2). The solid filter cake was dried under vacuum. The solid was then dissolved in EtOAc (1.2 L) and the solution heated to reflux for 10 min. -600 mL of solvent was removed by concentration under vacuum. An additional 600 322 mL of EtOAc was added and the process of refluxîng for 10 min followed by removal of 1 L of solvent was repeated. Finally, EtOAc (1 L) was added and the mixture was heated at reflux for 2 h. Upon cooling ovemight, the resulting solid was fïltered off, washing with EtOAc (1 x). This solid was then dried under vacuum at 60 °C for 4 h affordîng the product as a white solid (97.4 g, 78 %). 'H NMR (400 MHz, DMSO-î/₆) δ 13.01 (s, IH), 12.61 (s, IH), 8.17 - 8.05 (m, 2H), 8.01 (d, J = 1.0 Hz, IH), 7.69 - 7.58 (m, 4H), 7.57 - 7.45 (m, 2H), 7.31 - 7.23 (m, IH), 7.08 (d, J = 1.1 Hz, IH), 3.73 (dt, J = 11.2, 3.1 Hz, 2H), 3.20 - 2.92 (m, 3H), 1.66 (h, J = 4.2 Hz, 4H). LCMS m/z 456.0 [M+Hf.

Préparation of4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3-f]indazol- 7yl]benzoic acid (33) from S4

Step 1. Synthesis of ethyl 4flf2,2-dimethylpropanoyl)-5-(4fluorophenyl)-6-tetrahydropyran-4yl-pyrrolo[2,3-f]indazol-7-yl/benzoate (C58)

A mixture of l-[5-(4-fluorophenyl)-7-iodo-6-tetrahydropyran-4-yl-pyrrolo[2,3-f]indazoll-ylf2,2-dîmethyl-propan-l-one S4 (1.0 g, 1.83 mmol), (4-ethoxycarbonylphenyl)boronic acid (556.9 mg, 2.87 mmol), and Pd(dppf)Cl₂ (76.3 mg, 0.09 mmol) was placed under a nitrogen atmosphère. 1,4-dioxane (8.8 mL) and sodium carbonate (3.2 mL of 2 M, 6.4 mmol) were added and the mixture was heated at 90 °C for 30 min. Purification by silîca gel chromatography (05 % EtOAc in CH2CI2) gave a light tan solid. Minimal Et2O and heptane were added to the solid, and the white solid precipitate was fïltered off. The solid was dissolved in dîchloromethane (ca. 25 mL). MP-TMT resin (1.1 g) was added and the mixture stirred for 1 h at room température. The resin was fïltered off and the fîltrate concentrated in vacuo to afford the product as a white solid (681.7 mg, 62 %). ’H NMR (400 MHz, Chloroform-d) δ 8.45 (s,

IH), 8.21 (d, J = 7.8 Hz, 2H), 8.08 (s, IH), 7.58 (d, J = 8.0 Hz, 2H), 7.46 (dd, J = 8.0, 4.9 Hz,

2H), 7.35 (t, J = 8.2 Hz, 2H), 7.12 (s, IH), 4.48 (q, J = 6.9 Hz, 2H), 3.86 (dd, J = 11.3, 4.2 Hz,

2H), 3.23 (t, J = 11.7 Hz, 2H), 3.09 - 2.99 (m, IH), 1.90 - 1.77 (m, 2H), 1.64 (d, J = 13.2 Hz,

2H), 1.58 (s, 9H), 1.48 (t, J = 7.1 Hz, 3H). LCMS m/z 568.5 [M+Hf.

Step 2. Synthesis of 4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3-findazol-7yl]benzoic acid (33)

NaOH (6 mL of 1 M, 6.0 mmol) and piperidine (260 pL, 2.629 mmol) were added to a solution of ethyl 4-[l-(2,2-dimethylpropanoyl)-5-(4-fluorophenyl)-6-tetrahydropyran-4-ylpyrrolo[2,3-f]indazol-7-yI]benzoate C58 (682 mg, 1.20 mmol) in THF (14 mL) and MeOH (7 mL). The mixture was heated at 50 °C for 1 h. The solvent was concentrated, and the residue redissolved in minimal water. HCl (6 mL of 1 M, 6.0 mmol) was added and a precipitate formed. The solid was fïltered off and washed with excess water to afford the product as an off-white solid. (455.7 mg, 83 %). *H NMR (400 MHz, DMSO-î/₆) δ 13.02 (s, IH), 12.60 (s, IH), 8.11 (d, 323

J = 7.7 Hz, 2H), 8.00 (s, IH), 7.63 (t, J = 7.3 Hz, 4H), 7.51 (t, J = 8.4 Hz, 2H), 7.26 (s, IH), 7.07 (s, IH), 3.73 (d, J = 11.2 Hz, 2H), 3.15 - 3.07 (m, 2H), 3.05 - 2.96 (m, IH), 1.72 - 1.61 (m, 4H). LCMS m/z 456.4 [M+Hf.

Alternative Préparation of 4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3f]indazol-7-yl]benzoic acid (33) from S4

F

Step 1. Synthesis of ethyl 4-[l-(2,2-dimethylpropanoyl)-5-(4-fluorophenyl)-6-tetrahydropyran-4yl-pyrrolo[2,3-]] indazol- 7-yl]benzoate (C58)

To reactor A under nitrogen was added S4 (5.42 kg), 4-methoxycarbonyl benzene boronic acid (1.786 kg), Na₂CO₃ (2.986 kg), 1,4-Dioxane (36 L), and potable water (12.5 L). The agitator was started and reactor A was degassed with one vacuum / nitrogen cycle. Nitrogen was bubbled via the bottom of the reaction mixture with stirring at room température while venting the nitrogen via the top of the reactor for 1 h. Pd(dppf)Cl₂-CH₂Cl₂ adduct (0.186 kg) was charged as a solid to reactor A. 1,4-Dioxane (1 L) was degassed (nitrogen bubbling for 5 min), and used to rinse the solids off the walls of reactor A. Reactor A was heated to 74 °C78 °C for 3.5 h. The reaction was then held at 20 °C ovemight, and then heated to 38.1 °C. Potable water (24 L) was added to reactor A over 18 min, while maintaining the température at 36.0 °C to 38.1 °C. The slurry was cooled to 20 °C over 2.5 h and filtered (filtration time 25 min). The cake was washed with potable water (2 L x 2) and then was deliquored ovemight. The wet filter cake solid and CH₂C1₂ (25 L) was charged to reactor A. To a container was

324 charged NaCl (l.l kg) and potable water (9.9 kg). The contents were mixed to dissolve the NaCl. The brine solution was charged to reactor A. The agitator was started and the contents of reactor A were mixed at 22 °C for 15 min. The agitator was stopped and the layers separated for 22 min. The organic layer was removed (no émulsion). The aqueous layer was back extracted by charging CH₂C1₂ (5 L) to reactor A. The agitator was started and mixed for 15 min. The agitator was stopped and the phases settled for 15 min. The CH₂Cl₂ layer was removed and combined with the l^sl CH₂C1₂ layer. To reactor B was charged charcoal (1 kg) and the solution of product C58 in CH₂CI₂. The agitator was started and stirred at room température for 23.5 h. A filter was set with Celîte® plug and the contents of reactor B were filtered via the Celite® filter. The Celite® cake was washed with CH₂C1₂ (6 L). The CH₂C1₂ solution was concentrated to 2.5 volumes by vacuum distillation in two separate flasks. Heptanes (7 L) were charged to each flask while rotating, causing the formation of a thick slurry. Both flasks were held at room température overnight, and concentrated to 4 volumes. Each flask was cooled to 0-5 °C, and rotated for 1 h. The contents of each flask were combined and filtered. The cake was washed with a CH₂C1₂: heptanes (1:5) solution. The solids were loaded into trays and dried at 50 °C in a vacuum oven for 3 days, to afford the product C58 as a brown solid (5.3 kg, 88 % yield, 8.0 wt % 1,4-dioxane solvaté).

Step 2. Synthesis of 4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3-flindazol-7yl] benzoic acid (33)

Part A. Hydrolysis

To reactor A under nitrogen was added ethyl 4-[ 1-(2,2-dimethylpropanoyl )-5-(4fluorophenyl)-6-tetrahydropyran-4-yl-pyrrolo [2,3-f]indazol-7-yI] benzoate (C58) (5.2 kg), éthanol (26 L, 5 vol.), water (14.3 L, 2.7 equiv.), and 45 % KOH (6.12 kg, 49.1 mol, 5.2 equiv.). The agitator was started and the reaction mixture was heated to 70-75 °C for 1 h. The reaction was cooled to room température and filtered via a plug of Celite®. Reactor A was rinsed with éthanol (5 L, 1 vol.) and used to rinse the Celite®. To reactor A was added acetic acid (2.968 kg, 49.5 mol, 5.2 equiv.) and water 17 L, 3.3 vol.). The acetic acid / water was heated to 46 °C and stirred at 200 rpm. The solution of C58 in ethanoi was added over 22 min to the acetic acid / water to give a fine slurry. The température was 46.3 °C and the pH was 6.36. Acetic acid (1.176 kg, 19.7 mol, 2 equiv.) was added and the pH was 5.86 measured with a pH probe. The jacket was set with the foîlowing profile to hold at 50 °C for 9 h, cool to 20 °C, and hold at 20 °C overnight. The slurry was stirred at 20 °C for 6 h before filtering. The slurry was filtered for 24 h. Water was charged to wash the cake (16 L, 3 vol.), which was filtered for an additional day to afford compound 33 as a potassium sait (brown solid, approximately 80 % yield).

325

Part B. Free acid formation

To reactor A was added the wet 4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lHpyrrolo[2,3-f]indazol-7-yl]benzoic acid (33) potassium sait (3.4 kg). Potable water (44 L) was added to reactor A and the agitator was started. The mixture was stirred slowly at first and then at 133 rpm to give a ni ce slurry. IM HCl (7.4 L) (O.l équivalents excess based on an 80 % isolated yield of the potassium sait of compound 33) was charged to reactor A. Stirring was maintained for 3 h at 25 °C, and then left ovemight. The mixture was filtered on two filters by splitting the batch in half. After filtering for 8 h, the cake was washed with potable water (2 L) for each filter. The filtering continued ovemight, and the cake was dried with vacuum filtration for 20 h. Compound 33 was dried under vacuum for 2 days at 50 °C and then for 2 days at 30 °C to afford the product (free acid) as a brown solid (3.4 kg, 80 % yield).

Part C. Palladium Scavenging

To reactor A under nitrogen was charged compound 33 (3.4 kg, 7.47 mol), MeTHF (34 L), PhosphonicsS SPM32 (0.686 kg) (PhosphonicsS SPM32 = 3-Mercaptopropyl ethyl sulfide Silica, métal scavenging functionalized silica), and carbon (0.682 kg). The mixture was heated to 68 °C for 17 h with stirring. The mixture was cooled to 43 °C and filtered via a filter lined with a 2 inch silica gel pad. The silica was rinsed with MeTHF (6 L). A 2^nd treatment was carried out by charging SPM32 (0.68 kg), carbon (0.681 kg), and the filtrate of compound 33 in MeTHF to a 100 L reactor under nitrogen. MeTHF (4 L) was used to aid in the transfer of the solution of compound 33 in MeTHF back to the reactor. The stirring was initiated and the mixture was heated to 68 °C. The mixture was stirred for 23 h, cooled to 50-60 °C, and filtered as described above. This process was repeated two additional times. The filtrate was filtered via a 0.2 micron filter into a rotovap flask and concentrated to a wet solid. EtOH (8 L) was added and the vacuum distillation was continued to afford a solid. The solid was dried under vacuum at 50 °C ovemight to afford compound 33 (1.95 kg, S % éthanol solvaté).

Part D. Drying Procedure

To a flask containing compound 33 (1.95 kg, 8 wt % éthanol solvaté) was added anhydrous CH₂C1₂ (10 L). The mixture was distilled under vacuum to viscous slurry. CH₂C1₂ (10 L) was added and the mixture was distilled under vacuum again, to give a wet solid. CH₂C1₂ (10 L) was added to afford a slurry. The slurry was transferred to reactor A and additional CH₂CI₂ (10 L) was used to transfer the residual contents of the flask to reactor A. The agitator was started, and the slurry was heated to 37 °C, and held for 2 h at 35-37 °C. The slurry was then cooled to 18 °C over 30 min, and held at 18 °C for 30 min. The slurry was filtered and 326 washed with CH2CI2 (2 L x 2) at room température over 2 h. The filtered solid material was loaded into trays and dried in a vacuum oven at 70 °C ovemight. The solids were broke apart into a fine powder, and dried for an additional 4 h to afford compound 33 as a beige solid (1.36 kg, 72 % yield, corrected for EtOH solvaté, and 0.4 % water).

Alternative Préparation of 4~[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3f]indazol-7-yl]benzoic acid (33)

Step L Synthesis of 5-bromo-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-lH-indazole

5-bromo-6-iodo-1H- 5-bromo-6indazole ((tetrahydro-2Hpyran-4-yl)ethynyl)1H-indazole (C2)

Dispense 5-bromo-6-iodo-lH-indazole (Cl) (45.0 g, 139.35 mmol, 1 equiv) in éthanol (270 mL, 6 vol). Charge trimethyl((tetrahydro-2H-pyran-4-yl)ethynyl)silane (27.95 g, 153.28 mmol, 1.1 equiv) and potassium hydroxide 40% w/v solution (41,05 mL, 292.63 mmol, 2.1 equiv).

Evacuaie and sparge the reactor with nitrogen multiple times. Add palladiumbîs(triphenylphosphine) dichloride (0.978 g, 1.39 mmol, 0.01 equiv) and copper iodide (1.34 g, 6.97 mmol, 0.05 equiv) to the reaction. Evacuate and sparge the reactor with nitrogen multiple times. Heat the reaction to 75 °C. Upon reaction completion, cool the reaction and charge DCM (270ml, 6 vol) followed by an aqueous ammonium chloride solution [9.2wt%] (270 mL, 6 vol).Stop agitation and separate the layers. Wash the organic layer with an aqueous ammonium chloride [9.2wt%] solution (270 mL, 6 vol). Charge hydrogen chloride [0.125M] (60 mL, 0.054 equiv) to reactor containing the organic layer to obtain a pH of 5-6 and stir for N LT 30 minutes. Stop agitation and separate layers. Wash the organic layer with an aqueous NaCl solution [8.7 wt%] (270 ml, 6 vol). Distill the organic layer, charge DCM (270 mL, 6 vol) and continue the distillation, repeat twice. Heat the resulting slurry to reflux and add cyclohexane [90 ml, 2 vol]. Cool the reaction to 20 °C over 5 hours. Filter the slurry and rinse the reactor with a 1:1 mixture of DCM/ cyclohexane [l vol]. Dry the wet cake in a vacuum oven at 45 °C with nitrogen bleed. The product, 5-bromo-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-lH-indazole (C2)is isolated in 80% yield.

Examples of alternative reagents and solvents that can be used in Step 1 as described above are as follows:

327

Solvents: alcoholic solvents like l-butanol, isopropyl alcohol (IPA), THF/ alcohol mixtures, MeTHF/alcohols;

Base: NaOH, K2CO3, Na₂CO3, Cs₂CO₃ NaOtBu, KOtBu;

Catalysis: Pd(PPh₃)4;

Reaction without palladium using Cul or CuI/PPhj with KOH as base;

Reaction in DMF/ with DBU as base with cat H₂O.

Step 2. Synthesis of 5-(4-fluorophenyl)-6-(tetrahyàro-2H-pyran-4-yl)~l,5-dihydropyrrolo(2,3 findazole (Cl3)

W-(4-fl u o ro p h e ny I )-6-( (tetra h yd ro-2 H- py ra n-4-y I ) et hy n y I) 1H-indazol-5-amine

C12

Add sodium toY-butoxide, 97% (99.2 g, 1032.2 mmol, 2.1 equiv) to reactor containing éthanol (900 mL, 6 vol). Degas and sparge solution with nitrogen multiple times. Add 5-bromo6-((tetrahydro-2H-pyran-4-yl)ethynyl)-lH-indazole (C2) (150 g, 193.99 mmol, 1 equiv) and 4fluoroaniline (60.08g, 52.22 mL, 540.67 mmol, 1.1 equiv). Apply vacuum and nitrogen purge cycle 3 times

Add chloro(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-l, 1 '-biphenyl)[2-(2aminoethyl)phenyl] palladium(II) (11.796 g, 17.203 mmol, 0.035 equiv.) and degas and sparge with nitrogen NLT 3 times. Heat the reactor to 65 °C. Upon reaction completion, add acetic acid (140.2 g, 133.65 mL, 2334.7 mmol, 4.75 equiv) at 60 °C and continue to stir for NLT 3 hours. Upon reaction completion, cool the reactor to 20 °C and add NaOH [0.5M] (900 mL, 6 vol) and DCM (600ml, 4 vol) to reactor. Stop agitation and separate the layers. Back extract the aqueous layer with DCM. Combine the organic layers and distill the organic solution down to 3 volumes. Charge DCM (900 mL, 6 vol) to reactor and continue distillation; repeat the process two more times. Heat the reactor to 38 °C and add o-heptane (450 mL, 3 vol) over 2 hours. Cool the reactor down to 20 °C over 3 hours. Filter the slurry and rinse the wet cake a 1:1 ratio of DCM/ «-heptane (1 volume). Dry the wet cake to vacuum oven set to 45 °C. The product, 5-(4fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-I,5-dihydropyrroIo[2,3-f|indazole (C13), is isolated in 85% yield.

328

Examples of alternative reagents and solvents that can be used în Step 2 as described above are as foîlows:

Solvents: alcoholic solvents like 1-butanol, tert-butanol, isopropyl alcohol (IPA), tAmOH, THF, MeTHF, CPMe, Toluene, DMF, ACN, DMA, diglyme;

Base: NaOH, K₃PO₄, K₂CO₃,NaOtBu, KOtBu; NaOEt;

Catalysts in general ail générations of catalysis should work: PdtBuXPhos Gl-4 (tested); (PdOAc)₂ Pd(cinnamyl)Cl₂ with ligands: BrettPhos, SPHos, XPhos, XantPhos, dppf, JosiPhos; cataCXium® A (Note: cyclization of N-(4-fluorophenyl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl)1 H-indazol-5-amine to 5-(4-fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-l ,5-dihydropyrrolo[2,3fjindazole;

Reagents: Acids, Lewis acids like copper salts and heat.

Step 3. Synthesis of l-(5-(4-fiuorophenyl)-6-(tetrahydro-2H-pyran-4-yl)pyrrolo [2,3-f] indazol1 (5H)-yl)-2,2-dim ethylpropan-1-one

KOtBu THF

- ( 5-(4 -f I uo ro p h e ny I )-6-(tet ra hyd ro2 H- p yra n-4-yl ) p yrro lo [2,3-fj i n d azo I 1(5H)-yl)-2_r2-dimethyipropan-1one

5-(4-fluorophenyl)-6-(tetrahydro2H-pyran-4-yl)-1,5dihyd ropyrrolo[2,3-/]indazole

Dissolve 5-(4-fluorophenyl)-6-(tetrahydro-2H-pyran-4-yI)-1,5-dihydropyrrolo[2,3f]indazole (C13) (367.5 g, 1.09 mol, 1 equiv) in THF (5.15 L, 14 vol). Cool the reactor to - 6 °C and add KOtBu [2M in THF] (0.71 L, 1.3 equiv), Stir the solution for at NLT 20 minutes. Add trimethylacetyl chloride (0.193 L, 1.43 equiv) to reactor at -6 - 0 °C and stir the content for 1 hour at 0 °C. Upon reaction completion, heat the reactor to 18 -20 °C over I hour. Add an aqueous solution ofNaHCO₃ solution (101 g, 1.1 equiv 1.5 L, 4vol of water) and MtBE (1.5 L, 4 vol) to reactor. Stir the content for NLT 30 minutes at 20 °C. Stop agitation and separate the layers. Préparé an aqueous NaCl solution by mixing NaCl (301 g, 4.7 equîv) in purified water (1.5 L, 4 vol). Add the aqueous NaCl solution to the organic layer and stir for NLT 30 minutes. Stop agitation and separate the layers. Add MP-TMT resin (73.5 g, 20wt%) to reactor, heat the reactor to 50 °C and stir for NLT 12 hours. Filter the reactor content over a bed of celite and wash the celite with MtBE (0.7 L, 2 vol). Distill the organic fîltrate down to 2-3 volumes. Add methanol (0.91 L, 2.5 vol) to reactor and heat the reactor to 60 °C. Stir for I hour and add methanol (0.184 L, 0.5 vol) to the reactor. Cool the contents to 40 °C. Stir the contents for 1 hour

329 at 40 °C. Add methanol (1.64 L, 4.5 vol) over 4 hours. Cool the contents to 10 °C over at least 4 hours and âge the contents for at least 18 hours at 10 °C. Filter the hatch and rinse the wet cake with a mixture of methanol (1.38 L, 3.75 vol) and THF (0.46 L, 1.25 vol). Dry the wet cake at 45 °C under vacuum. The product, l-(5-(4-fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,3f]indazol-l(5H)-yl)-2,2-dimethylpropan- 1-one (C14), is isolated in 80% yield.

Examples of alternative reagents and solvents that can be used in Step 3 as described above are as follows:

Solvents: MeTHF, DCM;

Base: Li/ Na/ K Ο/Bu, Na / K/ LiOtAm.

Step 4. Synthesis of l-(5-(4-fhiorophenyl)-6-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,3-f] indazol! ( 5H)-yl)-2,2-dimethylpropan-1-one

1-(5-(4-fluorophenyl)-6-(tetrahydro-2H-pyran4-yl)pyrrolo[2,3-^ndazol-1(5H)-yl)-2.2dimethylpropan-1-one

-(5-(4-fluorophenyl}-7-iodo-6-(tetra hydro2H^yran-4M)pyrrolo[2,3-/;indazoî-1(5H)-yl)2,2-dirnethylpropan-1-one

Dissolve l-(5-(4-fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,3-f]indazol1 (5H)-yl)-2,2-dimethylpropan-l-one (C14) (30.76 g, 73.3 mmol, 1 equiv, limîting reagent) in methylene chloride (307.6 mL, 10 vol). Cool the reactor down to -5 °C and add Niodosuccinimide (18.23 g, 76.99 mmol, 1.05 equiv.) at -5.0-0 °C. Stir reaction at -5 °C for NLT 30 minutes. Upon reaction completion, add an aqueous sodium thiosulfate solution (Na₂S₂O₃· 5H₂O 9 g, 0.037 mmol, 0.5 equiv in purified water (0.1 L, 2.4 vol) to the reaction at 0 °C. Stir the content for NLT 30 minutes at 0 °C followed by warm up to 20 °C. Stop agitation and separate layers. Add an aqueous NaHCO₃ solution (NaHCO₃ 8.7g, 0. Immol,1.3 equiv dissolved in purified water (0.12 L, 3.7 vol) to the organic layer. Stir for NLT 30 minutes, stop agitation and separate layers. Add an aqueous NaCI solution (NaCI 20 g, 0.34mmol, 4.7 equiv) in purified water (133 mL, 4.3 vol). Stir for NLT 30 minutes, stop agitation and separate layers. Distill the organic layer down to 2-3 volumes. Add THF (0.15 L, 5 vol) to reactor and distill down to 2-3 volumes, repeat 2-3 times. Add THF (up to 2 volumes) to the reactor to obtain a total of 4 volumes. Heat to slurry to internai température of 56 -58 °C. Add MeOH (0.061 L, 2 vol) at 56 °C over 1 hour to reactor. Cool the reactor content down to 52 °C and stir for NLT for 30 minutes. Add MeOH (0.25 L, 8 vol) over 3 hours at 52 °C to reactor. Cool the slurry down to

330 °C at a 5 °C/h rate. Stir the reactor content at 20 °C for NLT 30 minutes. Filter the slurry and rinse the wet cake with MeOH (0.03 L, 1 vol) Dry the wet cake under vacuum at 60 °C. The product. l-(5-(4-fluorophenyl)-7-iodo-6-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,3-f]mdazol-l(5H)yl)-2,2-dimethylpropan-l-one (S4), is isolated in 90% yieid.

Examples of alternative solvents that can be used in Step 4 as described above are THF,

MeTHF, CAN, EtOAc, DMF, dichloroethane (DCM).

Step 5. Synthesis of methyl 4-(5-(4fluorophenyl)-!-pivaloyl-6-(tetrahydro-2Hpyran-4-yl)-l,5 dihydropyrrolo[2,3-f] indazol- 7-yl)benzoate

1-(5-(4-fliJoropheny[)-7-ioda-6(tetra hyd ro-2 H- pyran-iyl) pyrro I o[2,3- fl i nd azol-1 (5 H) -yl)2,2-dimethylpropan-1 -one (4(methoxycarbanyl) phenyl) boronic acid methyl 4-(5-(4-fluorophenyl)-1 pivaioyl-6-(!etrahydro-2 Hpyran-4-yl)-1,5dihydropyrrolof2,3- fl indazol-7yl)benzoate

Add l-(5-(4-fluorophenyl)-7-iodo-6-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,3-f]mdazoll(5H)-yl)-2,2-dimethylpropan-l-one (S4) (10.0 g, 1S.3 mmol, 1.0 eq.), 4-(methoxycarbonyl)phenyl)boronic acid (3.80 g, 21.1 mmol, 1.15 eq.), and tetrahydrofuran (100 mL, 10 vol.) to a reactor and begin agitation. Préparé a solution of potassium carbonate in water by adding potassium carbonate (8.11 g, 58.7 mmol, 3.2 eq.) to water (70 mL, 7 vol.) at 25 °C in a separate vessel. Deoxygenate the mixture using three vacuum-nitrogen cycles. Add the aqueous potassium carbonate solution to the reactor. Deoxygenate the resulting bîphasic mixture with three successive vacuum-nitrogen cycles. In a separate vessel, add triethylamine (74 mg, 0.73 mmol, 0.04 eq.) to a mixture of Pd(dppf)Cl₂ (0.30 g, 0.37 mmol, 0.020 eq.) and tetrahydrofuran (10 mL, 1 vol.). Deoxygenate using three vacuum-nitrogen cycles and the agitate the mixture for -1-2 h. Add the catalyst slurry to the reactor, rinsing forward with additional tetrahydrofuran (10 mL, 1 vol.) [Total tetrahydrofuran (120 mL, 12 vol) in reaction mixture], and perform an additional three vacuum-nitrogen cycles. Heat the reaction to to 65 °C. Upon reaction completion, cool the reactor contents to 55 °C and separate the layers. Add tetrahydrofuran (180 mL, 18 vol.) and Celite (100 wt %, 10.00 g) to the reactor and agitate at 55 °C for 1 hour. Filter the reaction mixture and rinse the cake with tetrahydrofuran (20 mL, 2 vol.). Charge SEM26 (2 g; 20 wt%) to the reactor and heat the mixture to 30-35 °C for NLT 18 hours. Filter the reaction mixture. Distill the fïltrate down to 5 volumes. Add THF (150 mL, 15 vol.) and distill down to 331

-7-8 volumes. Heat the reactor contents to 60-65 °C. Cool reactor contents to 50 °C. Add éthanol (140 mL, 14 vol.) over 2-3 hours at 50 °C and continue to stir for 30 min. Cool the mixture to 10 °C at a rate of 5 °C / h. Stir the slurry at 10 °C for NLT 1 h and filter the mixture. Rinse the wet cake with éthanol (20 ml, 2 x 1 vol). Dry the solids under vacuum at 65 °C for NLT 12h. The product, methyl 4-(5-(4-fluorophenyl)-l-pivaloyl-6-(tetrahydro-2H-pyran-4-yl)l,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoate (C58), is isolated in 80% yield.

Ex amples of alternative reagents and solvents that can be used in Step 5 as described above are as follows:

Solvents: Dioxane, MeTHF, IPA, toluene, ACN, DMSO, EtOH;

Catalyst Monodentate ligands: PCy₃ P(tBu)₃, DavePhos, SPhos Pd(PPhj)₂C12, Xphos, CataCXium; Pd(AmPhos)Cl_2i RuPhos;

Bidentate ligands: Pd(dippf)Cl₂, Pd(dtbpf)Cl₂, Pd(DPEPhos)Cl₂. Pd(dppf)Cl₂-CH₂Cl₂, Pd(Xantphos)Cl₂, Pd(dppb)Cl₂;

Base: K₂CO₃, Na₂CO₃. K3PO4.

Step 6. Optîonal recrystcdlization procedure to purge residual aryl dimer

Charge the methyl 4-(5-(4-fluorophenyl)-l-pivaloyl-6-(tetrahydro-2H-pyran-4-yl)-l,5dihydropyrrolo[2,3-fjindazol-7-yl)benzoate to a reactor. Add THF (9 vol.) and heat the reactor contents to 60 °C .Cool reactor contents to 50 °C. Add éthanol (18 vol.) over 2-3 hours. Stir the resulting thm slurry at 50 °C for 30 min. Cool the slurry to an internai temp. of 10 °C at a rate of 5 °C / h. Stir the slurry at 10 °C for NLT 1 h Filter the mixture

Rînse the wet cake with éthanol (2 x 1-2 V) 1 (2 x 1-2 V) Dry the solids under vacuum at 65 °C for NLT 12h. The product, methyl 4-(5-(4-fluorophenyl)-I-pivaloyl-6-(tetrahydro-2Hpyran-4-yl)-l,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoate, is isolated in 85% yield

methyl 4-(5-(4-f!uorophenyl)-1-pivaloyl6 - ( tet ra h yci ro-2 H-py ra n -4-y I ) -1,5dihydropyrrolo[2,3-f|indazol-7yljbenzoate

Add methyl 4-(5-(4-fluorophenyl)-l -pivaloyl-6-(tetrahydro-2H-pyran-4-yl)-1,5dihydropyrrolo[2,3-f|indazol-7-yI)benzoate (C58) (25.1 g, 45.337 mmol, 1 equiv, limiting

332 reagent) and THF (326.3 mL, 13 vol) to reactor. Add sodium hydroxide [2N] (5.44 g, 68.0 mL, 136.01 mmol, 3 equiv) to reactor and heat to 58 °C. Upon reaction completion, cool reactor to 20 °C. Add water (75.3 mL, 3 vol), acetic acid (10.89 g, 10.38 mL, 181.35 mmol, 4 equiv.) and 2MeTHF (251 mL, 10 vols) to reactor and stir for NLT 30 minutes. Stop agitation and separate layers. Add water (75.3 mL, 3 vol) to organic layer and extract. Separate layers and add an aqueous 6.5 wt% sodium chloride solution (NaCi 8.2g, 0.14mmol, 3.1 equiv) in water (0.120 L, 4.7 vol) to the organic layer. Stir for NLT 30 minutes, then stop agitation and separate layers. Distill the organic layer down to 2-3 volumes. Add EtOH (0. 176 mL, 7 vol) to reactor and continue distillation. Add EtOH (0.150 L, 6 vol) and water (25.1 mL, 1 vol) and distill the slurry down to 2-3 volumes. Add EtOH (0.150 L, 6 vol) and water (25.1 mL, 1 vol) to reactor and continue distillation down to 3 volumes. Add EtOH (0.150 L, 6 vol) and water (25.1 mL, 1 vol) to reactor and stir for NLT 30 minutes at 40 °C. Cool the reactor down to 20 — 25 °C at a 5 °C/h rate. Stir the reactor content for at least 30 minutes at 20 °C. Filter the slurry and rinse the wet cake with a EtOH/ H₂O 1:1 mixture (50 ml, 2 vol).Transfer the wet cake to vacuum oven set to 66 °C and dry the material for at NLT 12 hours. The product, 4-(5-(4-fluorophenyl)-6(tetrahydro-2H-pyran-4-yl)-l,5-dihydropyrrolo[2,3-f]indazol-7-yI)benzoic acid (Compound 33), is isolated in 90% yield.

Examples of alternative reagents and solvents that can be used in Step 5 as described above are as follows:

Solvents: MeTHF, EtOH, MeOH, IPA;

Base: LiOH, NaOH, KOH Work up: acetic acid, HCl.

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Compound 34 (2S,3S,4S, 5R)-6-[4-[5-(4-fluorophenyl)-6~tetrahydropyran-4-yl-l I-I-pyrroîo[2,3-f] indazol-7yljbenzoyl]oxy-3,4,5-trihydroxy-tetrahydropyran-2-carboxylic acid (34)

Step 1. Synthesis of allyl (2S,3S,4S,5R)-6-[4-[5-(4-fluorophenyl)-6-tetrahydropyran~4-yl-lHpyrrolo[2,3-f]indazol-7-yl]benzoyl] oxy-3,4,5-trihydroxy-tetrahydropyran-2-carboxylate (C59)

MeCN (12 mL) and NMM (210 pL, 1.91 mmol) were added to a mixture of 4-[5-(4fluorophenyl)-6-tetrahydropyran-4-yl-lH-pynOlo[2,3-f]indazol-7-yl]benzoic acid 33 (449 mg, 0.96 mmol), allyl (2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-carboxylate (224 mg, 10 0.96 mmol), and HATU (370 mg, 0.97 mmol). The reaction was allowed to stir overnight at room température. The mixture was diluted in CH₂C1₂ and washed with 50 % saturated sodium bicarbonate. The organic phase was passed through a phase phase separator and concentrated in vacuo. Silica gel chromatography (Gradient: 0-10 % méthanol in CH₂C1₂) afforded tire product which was used in the subséquent step without further purification (228 mg, 35 %). LCMS m/z 15 672.5 [M+H]⁺.

Step 2. Synthesis of(2S,3S,4S,5R)-6-[4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lHpyrrolo[2,3-f] indazol- 7-yl]benzoyl]oxy-3,4,5-trihydroxy-tetrahydropyran-2-carboxylic acid (34) 334

To a solution of allyl (2S,3S,4S,5R)-6-[4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yllH-pyrrolo[2,3-f]indazol-7-yl]benzoyl]oxy-3,4,5-Îrihydroxy-tetrahydropyran-2-carboxylate (54 mg, 0.08 mmol) in CH2CI2 (7.2 mL) was added morpholine (14 pL, 0.16 mmol). The solution was purged with nitrogen, then Pd(PPh₃)4 (3 mg, 0.003 mmol) was added. The mixture was allowed to stir for 30 min. MP-TMT resin was added and the mixture stirred for an additional 4 h. The mixture was fïltered and concentrated. Purification by reversed phase chromatography (Gradient: 0-100% MeCN in water with a 0.2 % formic acid modifier) afforded the desired product (20.3 mg, 42 %). ‘H NMR (300 MHz, DMSO-</₆) δ 12.55 (s, IH), 8.16 - 8.10 (m, 2H), 7.94 (d, J = 1.0 Hz, IH), 7.71 - 7.61 (m, 2H), 7.60 - 7.52 (m, 2H), 7.50 - 7.39 (m, 2H), 7.22 (t, J = 1.2 Hz, IH), 7.01 (d, J = 1.1 Hz, IH), 5.65 - 5.57 (m, IH), 5.50 (d, J = 4.3 Hz, IH), 5.31 - 5.19 (m, IH), 3.77 (d, J = 8.7 Hz, IH), 3.66 (d, J = 10.9 Hz, 2H), 3.40 - 3.32 (m, 4H), 3.11 - 2.89 (m, 3H), 1.65 - 1.48 (m, 4H). LCMS m/z 632.5 [M+H]⁺.

Compound 35

4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3-ff indazol-7-yl]-3-methylbenzoic acid (35)

A mixture of l-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yI-7-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyrrolo[2,3-fJindazol-l-yl]-2,2-dimethyl-propan-l-one S5 (257.2 mg, 0.39 mmol), methyl 4-bromo-3-methyï-benzoate (202.3 mg, 0.88 mmol), and Pd(dppf)Cl₂ (37.8 mg, 0.05 mmol) was placed under a nitrogen atmosphère (evacuation/nitrogen cycles x 3). 1,4dioxane (1.9 mL) and sodium carbonate (685 pL of 2 M, 1.4 mmol) were added. The mixture was heated at 90 °C for 45 min. Upon cooling, the mixture was diluted with CH₂C1₂ (5 mL), fïltered through a pad of Celite® and the fîltrate was concentrated în vacuo. The residue was dissolved THF (4.2 mL) and MeOH (2.1 mL) and sodium hydroxide (2.3 mL of 1 M, 2.31 mmol) added. The mixture was then heated at 50 °C for 2 h. The solvent was removed under vacuum and re-dissolved in minimal water. HCl (2.3 mL of I M, 2.3 mmol) was added and the mixture was concentrated in vacuo. Purification by silica gel chromatography (Gradient: 5-20 %

335

EtOAc in CH2CI2, containing l % AcOH) afforded the product as a white solid (24.8 mg, 14 %). ‘H NMR (400 MHz, DMSO-î7₆) δ I2.97 (s, IH), 12.52 (s, IH), 8.00 (s, 2H), 7.89 (d, J = 7.7 Hz, IH), 7.67 - 7.58 (m, 2H), 7.50 (t, J = 8.5 Hz, 2H), 7.45 (d, J = 7.9 Hz, IH), 7.16 (s, IH), 6.83 (s, IH), 3.74 - 3.61 (m, 2H), 3.10 - 2.97 (m, 2H), 2.88 - 2.73 (m, IH), 2.18 (s, 3H), 1.76 - 1.51 (m, 3H), 1.44-1.31 (m, IH). LCMS m/z 470.44 [M+H]⁺.

Compound 36

4f5-(4-fluorophenyl)-6-tetrahydropyran-4-yl- ! H-pyrrolo[2,3-f] indazol- 7-yl] benzenesulfonic

Step L Synthesis of l-(benzenesulfony})-5-(4-fliiorophenyl)-6-tetrahydropyran-4-yl-7-(4,4,5,5te trame thyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-ffndazole (C60)

A flask containing l-(benzenesulfonyl)-5-(4-fluorophenyl)-7-iodo-6-tetrahydropyran-4y 1-pyrrolo[2,3-f]indazole S6 (96.7 mg, 0.16 mmol) and Pd(dppf)Cl₂ (5.2 mg, 0.007 mmol) was purged with nitrogen. m-Xylene (760 pL) was added and the solution degassed. Et₃N (80 pL) followed by 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (36 pL, 0.25 mmol) were added and the mixture was heated at 150 °C for 1 h. The mixture was filtered and concentrated in vacuo. Purification by silica gel chromatography (Gradient: 0-5 % EtOAc in CH₂C1₂) afforded the product as a light yellow solid, with an 8 % impurity from reduced starting material which coeluted with the product. The product was used in the subséquent step without further purification (67.7 mg, 64 %). 'H NMR (400 MHz, Chloroform-d) δ 8.93 (s, IH), 8.13 (s, IH), 8.00 (d, J =

336

7.9 Hz, 2H), 7.52 (t, J = 8.3 Hz, 1 H), 7.41 (t, J = 7.7 Hz, 2H), 7.01 (s, 1 H), 4.02 (dd, J = 11.5, 4.1 Hz, 2H), 3.32 (t, 11.7 Hz, 2H), 3.14-3.03 (m, IH), 2.49 - 2.36 (m, 2H), 1.63 - 1.59 (m, 2H),

1.53 (s, 12H). LCMS m/z 602.4 [M+H]⁺.

Step 2. Synthesis of 2,2,2-trifluoroethyl 4-[l-(benzenesulfonyl)-5-(4-fluorophenylh6tetrahydropyran-4-yl-pyrrolo[2,3-ff îndazol-7-yl]benzenesulfonate (C61)

A solution of 2,2,2-trifluoroethyl 4-bromobenzenesulfonate (24 mg, 0.08 mmol), 1(benzenesulfonyl)-5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-7-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyrrolo[2,3-f]indazole C60 (50 mg, 0.08 mmol), sodium carbonate (112 pL of 2 M, 0.2 mmol) and Pd(dppf)CL (5.9 mg, 0.007 mmol) in 1,4-dioxane (150 pL) was purged with nitrogen, and the reaction was heated at 90 °C for 1.5 h. Upon cooling, water and CH2CI2 were added and the layers separated using a phase separator. The organic layer was concentrated in vacuo and purified by silica gel chromatography (Gradient: 0-20 % EtOAc in dichloromethane) to afford the product (17.5 mg, 26 %). LCMS m/z 714.4 [M+H]^-1.

Step 3. 4-[5-(4fluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3-f]indazol-7yl] benzenesulfonic acid (36)

Piperidine (4.1 mg, 0.05 mmol) and NaOH (61 pL of 2 M, 0.12 mmol) were added to a solution of 2,2,2-trifluoroethyl 4-[l-(benzenesulfonyl)-5-(4-fluorophenyl)-6-tetrahydropyran-4yl-pyrrolo[2,3-f]indazol-7-yl]benzenesulfonate C61 (17.5 mg, 0.02 mmol) in MeOH (87.5 pL) and THF (175 pL). The reaction was heated to 55 °C for 1 h, then stirred overnight at room temperature. The mixture was concentrated in vacuo, water (1 mL) was added and the mixture acidified to pH 3 using 1 M HCl. The mixture was then concentrated in vacuo and purified by reversed phase chromatography (Cl8 column. Gradient: 0-100 % MeCN în water with 0.1 % foi-mic acid) to afford the product (9.4 mg, 73 %). ’H NMR (300 MHz, MethanoL^) Ô 8.50 (s, IH), 8.03 - 7.96 (m, 2H), 7.63 - 7.49 (m, 4H), 7.41 (t, J = 8.5 Hz, 2H), 7.29 (s, 1 H), 7.11 (d, J = 1.1 Hz, IH), 3.86 - 3.75 (m, 2H), 3.25 - 3.16 (m, 2H), 3.11 - 3.04 (m, IH), 1.88 - 1.65 (m, 4H). LCMS m/z 492.4 [M+H]⁺.

Compounds 3 7-44

Compounds 37-44 were prepared from S6 in two steps according to the method described for compound 33 from S6 (as indîcated by Method B). In some examples, alternative Suzuki coupling conditions are used, as indîcated by method A. Purification of the final product was perfonned using HPLC or normal pressure reverse phase chromatography.

Coupling conditions for Suzuki coupling step in compounds 37-44:

Method A: Step 1. boronîc acid or ester, XPhos Pd G3, K3PO4, 1,4-dioxane-water, 85 °C, 1 h. Step 2. NaOH, THF-MeOH.

337

Method B: Step 1. boronic acid or ester, Pd(dppf)C12, 2M Na2CO₃, 1,4-dioxane, 90 °C, 1 h. Step 2. NaOH, THF-MeOH

Table 5. Method ofpréparation, structure, physicochemical data for compounds 37-44

Compound	Method/Product	Boronic acid or ester	*H NMR; LCMS m/z [M+H]
37	Method A from S6 0. A OH Jl f w H / C L ί H p aa>An \—/ fl F	O^OMe JÎJ f'AA A HO OH	NMR (400 MHz, M éthanol A4) δ 8.00 (d, J = 9.9 Hz, 2H), 7.90 (d, J = 10.0 Hz, IH), 7.64 (t, J = 7.5 Hz, IH), 7.60 -7.50 (m, 2H), 7.41 (t, J = 8.5 Hz, 2H), 7.16 (s, 2H), 3.85 3.75 (m, 2H), 3.21 (t, J = 11.4 Hz, 2H), 3.04-2.92 (m, IH), 1.86-1.62 (m, 4H). LCMS m/z 474.7 [M+H]+.
38	Method B from S6 X-OH F. J rS H n /—\ â L ιΓ Va p fl F	O^OMe A HO OH	lHNMR (400 MHz, Methanol-^) δ 8.10 (t, J = 7.9 Hz, IH), 7.99 (s, IH), 7.53 (dd, J = 8.6, 4.8 Hz, 2H), 7.47 - 7.33 (m, 5H), 7.13 (s, 1 H), 3.83 (dd, J = 11.4,3.5 Hz, 2H), 3.24 (t, J = 11.8 Hz, 2H), 3.14-3.04 (m, IH), 1.83 (qd, J = 13.1, 3.9 Hz, 2H), 1.71 (d, J = 12.6 Hz, 2H). LCMS m/z 474.4 [M+H]’.
39	Method B from S6 VoH F J Fv H / \ Â L l[ Va p \---/ fl F	0^.0 Me :p A HO OH	’HNMR (400 MHz, MethanolA) δ 8.00 (s, IH), 7.88 (t, J = 7.4 Hz, IH), 7.60-7.50 (m, 2H), 7.47 - 7.37 (m, 3H), 7.20 (s, IH), 7.16 (s, IH), 3.82 (d. J = 11.5 Hz, 2H), 3.28-3.18 (m, 2H), 3.06-2.94 (m, III), 1.85 - 1.64 (m, 4H). LCMS m/z 492.4 [M+H]'.
40	Method B! from S6	0 As HO OH	’H NMR (400 MHz, Methanol-rf4) § 8.01 (s, IH), 7.98 (s, IH), 7.78 (d, J = 8.8 Hz, IH), 7.54-7.48 (m, 2H), 7.45 (d, J = 8.6 Hz, IH), 7.38 (t, J = 8.4 Hz,

338

CompOlllld	Method/Product	Boronic acid or ester	lH NMR; LCMS m/z [M+H]+
	\ 0 H n. T £ VX p F		2H), 7.33 (s, 111),7.14 (s, IH), 3.86 (dd, J = 10.7,2.8 Hz, 2H), 3.30 -3.22 (m, 2H), 3.11 -3.00 (m, IH), 1.90- 1.76 (m, 2H), 1.72 (d, J = 12.6 Hz, 2H). LCMS m/z 474.4 [M+H]'.
41	Method A2 from S6 O H n x JL £ /—\ p F	0 ,B. O 0	‘H NMR (400 MHz, M éthanol-ί/4) δ 8.15 (s, IH), 8.10 (d, J = 7.8 Hz, IH), 7.98 (s, IH), 7.74 (d, J = 7.5 Hz, IH), 7.64 (t, J = 7.7 Hz, IH), 7.54 (dd, J = 7.9,5.1 Hz, 311),7.41 (t, J = 8.5 Hz, 2H), 7.26 (s, IH), 7.14 (s, IH), 3.80 (d, J = 11.7 Hz, 2H), 3.21 (t, J = 11.7 Hz, 2H), 3.09-2.98 (m, IH), 1.87- 1.75 (m, 211), 1.70 (d, J= 12.9 Hz, 2H). LCMS m/z 456.4 [M+H]+.
42	Method B from S6 °Ύ0Η F\ X /XX H X X I /—( P Q F	O^OMe X ,F N Y |l J XBX	‘H NMR (400 MHz, Methanol-i/4) δ 8.64 (s, IH), 8.00 (s, IH), 7.94 (d, J = 10.9 Hz, IH), 7.54 (dd. J = 8.5, 4.8 Hz, 2H), 7.46 7.37 (m, 3H),7.I5(s, IH), 3.88 - 3.78 (m, 2H), 3.25 (td,J= 11.2,3.3 Hz, 2H), 3.09 (tt, J = 11.0,4.8 Hz, IH), 1.85 - 1.70 (m, 4H). LCMS m/z 475.7 [M+H]-.

339

Compound	Met h od/Product
43	Method B from S6 J/oh H N\\ JL L /—( P 0 F
44	Method B from S6 n \ < ï L /—( p Φ F

Boronic acid or ester	'H NMR; LCMS m/z [M+H]+
F O HO OH	'H NMR (400 MHz, Methanol-i/4) δ 8.01 (d, J = 6.9 Hz, IH), 7.98 (s, IH), 7.73 -7.68 (m, IH), 7.53 (dd, J = 8.5,4.8 Hz, 2H), 7.39 (s, 3H), 7.26 (s, IH), 7.13 (s, IH), 3.81 (dd, J = 12.5, 3.3 Hz, 2H), 3.22 (t, J = I1.7Hz, 2H),3.07-2.97 (m, IH), 1.86 - 1.67 (m, 4H). LCMS m/z 474.4 [M+H]\
O^xOMe X ,„Me N -f n J .B.	'H NMR (400 MHz, Methanol-i/4) δ 8.61 (s, IH), 8.02 (s, IH), 8.00 (s, IH), 7.55 (dd, J = 8.6, 4.8 Hz, 2H), 7.43 (t, J = 8.4 Hz, 2H), 7.32 (s, IH), 7.16 (s, IH), 3.87 -3.79 (m, 2H), 3.28-3.19 (m, 2H), 3.06 (dt, J = 11.1, 5.8 Hz, IH), 2.76 (s, 3H), 1.85 - 1.68 (m, 4H). LCMS m/z 471.4 [M+H]+.

Purification by reversed-phase HPLC. Method: Cl 8 Waters Sunfire column (30 x!50 mm, 5 micron). Gradient: 10-100 % MeCN in H2O with 0.2 % formic acid.

Purification by reversed-phase chromatography on a Cl 8 column. Gradient: 10-100 %

MeCN in H₂O Gradient: 10-100 % MeCN in H₂O.

340

Compound 45

4-[8-fluoro-5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3-fj indazol- 7-yl] benzoic

Step 1. Synthesis of 5-bromo-7-fluoro-6-(2-tetrahydropyran-4-ylethynyl)-lH-indazole (C63)

DMF (12 mL) was added to a vial containing 5-bromo-7-fluoro-6-iodo-lH-indazole C62 (2.0 g, 5.87 mmol) under a nitrogen atmosphère. The reaction mixture was purged with nitrogen for an additional 10 min. 4-Ethynyltetrahydropyran (845 mg, 7.67 mmol), Et₂NH (2 mL, 19.3 mmol) PdCLiPPhA (210 mg, 0.30 mmol) and Cul (83 mg, 0.44 mmol) were successively

341 added, and the mixture heated to 90 °C ovemight. The mixture was then concentrated to dryness, and then water and CH₂CI₂ were added. The organic phase was separated using a phase separator, then concentrated in vacuo. Purification by silica gel chromatography (Eluent: EtOAc in heptanes) afforded the product 5-bromo-7-fluoro-6-(2-tetrahydropyran-4-ylethynyI)-lHindazole (1.32 g, 70 %). LCMS m/z 323.1 [M+H]⁺.

Step 2. Synthesis of 7-fluoro-N-(4-fluorophenyl)-6-(2-tetrahydropyran-4-ylethynyl)-IH-indazol5-amine (C64)

NaOtBu (2.54 g, 26.4 mmol) was added to a solution of 5-bromo-7-fluoro-6-(2tetrahydropyran-4-ylethynyl)-lH-indazole C63 (4.78 g, 14.8 mmol) and 4-fluoroaniline (2.1 mL, 22.2 mmol) in tBuOH (80 mL). The mixture was purged with nitrogen for 10 min. tBuXPhos Pd G1 (365 mg, 0.53 mmol) was added and the reaction purged with nitrogen for an additional 10 min, then heated to 70 °C for 1 h. Water and CHjCb were added and the phases were separated on a phase separator. Purification by silica gel chromatography (Eluent: Ethyl acetate in CH₂C1₂) afforded the product (4.48 g, 86 %). ’H NMR (400 MHz, DMSOZ₆) δ 13.55 (s, 1 H), 8.11 - 7.84 (m, IH), 7.49 (s, IH), 7.24 (s, IH), 7.11 - 7.01 (m, 2H), 7.01 - 6.88 (m, 2H), 3.70 (dt, J = 10.2, 4.5 Hz, 2H), 3.40 (t, J = 9.9 Hz, 2H), 2.91 (dt, J = 9.2, 4.8 Hz, IH), 1.75 (dd, J = 10.9, 5.6 Hz, 2H), 1.50 (qd, J = 12.8, 10.8, 6.0 Hz, 2H).

Step 3. Synthesis of8-fluoro-5-(4-fluorophenyl)-6-tetrahydropyran-4-y/-lH-pyrrolo[2,3f] indazole (C65)

A solution of 7-fluoro-N-(4-lluorophenyl)-6-(2-tetrahydropyran-4-ylethynyl)-lHindazol-5-amine C64 (4200 mg, 11.9 mmol) in DMSO (17 mL) was heated at 150 °C in a microwave for 2 h. Water and EtOAc/Et₂O (1:1) were added. The aqueous layer was washed with EtOAc and the organic layers were combined, then dried with Na₂SO₄. The organic layer was concentrated in vacuo. Purification by silica gel chromatography (Eluent; Ethyl acetate in CH₂C1₂) afforded the product.

(3750 mg, 89 %). ^lH NMR (400 MHz, DMSO-î/₆) δ 13.10 (s, IH), 8.12 - 8.00 (m, IH), 7.57 (dd, J = 8.5, 5.2 Hz, 2H), 7.48 (t, J = 8.4 Hz, 2H), 7.03 (s, IH), 6.60 (s, IH), 3.85 (d, J = 11.4 Hz, 2H), 3.24 (q, J = 10.8, 8.9 Hz, 2H), 2.91 - 2.76 (m, IH), 1.70 (dd, J = 8.1, 3.2 Hz, 4H).

Step 4. 2-[8-fiuoro-5-(4-fluorophenyl)-6-ietrahydropyran-4-yl-pyrrolo[2,3-f] indazol-1yl]sulfonylethyl-trimethyl-silane (C66)

KOtBu (362 mg, 3.23 mmol) was added to a solution of 8-fluoro-5-(4-ftuorophenyl)-6tetrahydropyran-4-yl-IH-pyrrolo[2,3-f]indazole C65 (922 mg, 2.51 mmol) in THF (10.8 mL) and the réaction was stirred for 10 min. The reaction was then cooled on an ice bath and 2trimethylsilylethanesulfonyl chloride (473 pL, 2.50 mmol) was added. The reaction was stirred ovemight at room température. Water and CH₂C1₂ were added, and the layers separated using a 342 phase separator. The organic layer was concentrated in vacuo and purified by silica gel chromatography (Gradient: 0 - 100 % EtOAc in dichloromethane) to afford the product as a mixture of regioisomers, which was used in the subséquent step without séparation. (700 mg, 44 %). LCMS m/z 518.4 [M+Hf.

Step 5. 2-[8-fluoro-5-(4-fluorophenyl)-7-iodo-6-tetrahydropyran-4-yl-pyrrolo[2,3-f]indazol-1 yl]sulfonylethyl-trimethyl-silane (C6 7) l-iodopyrrolidine-2,5-dione (292 mg, 1.30 mmol) was added portion-wise to a solution of 2-[8-fluoro-5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-pyrrolo[2,3-f]indazol-lyljsulfonylethyl-trimethyl-silane C66 (700 mg, 1.35 mmol) in CH2CI2 (17.6 mL) at 0 °C. The reaction was allowed to stir at room température for 2 h. The mixture was quenched with IM Na₂SO₃. Water and CH2CI2 were added, and the phases were separated on a phase separator. Purification by silica gel chromatography (0 - 100 % EtOAc/dichloromethane) afforded the product 2 (352 mg, 34 %). LCMS m/z 644.3 [M+H] \

Step 6. 4-[8-fluoro-5~(4-fluoiOphenyl)-6-tetrahydropyran-4~yl-l-(2trimethylsilylethylsulfonyl)pyrrolo[2,3-f]indazol-7-yl/benzoate (C68)

A mixture of 2-[8-fluoro-5-(4-fluorophenyl)-7-iodo-6-tetrahydropyran-4-yl-pyrrolo[2,3f] indazol-l-yl]sulfbnylethyl-trimethyl-silane C67 (72 mg, 0.08 mmol), (4benzyloxycarbonylphenyl)boronic acid (41.9 mg, 0.16 mmol), sodium carbonate (122 pL of 2 M, 0.24 mmol) and Pd(dppf)Cl₂ (6.2 mg, 0.008 mmol) in 1,4-dioxane (328 pL) was stirred at 90 °C for 1.5 h. Water and CH₂C1₂ were added, and layers separated in a phase separator. The organic layer was concentrated to afford the product, which was used in the subséquent step without further purification (73 mg, 69 %). LCMS m/z 728.5 [M+H]⁺.

Step 7. Synthesis of 4-[8-fluoro-5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3f]indazol-7-yl]benzoic acid (C69)

A solution of benzyl 4-[8-fluoro-5-(4-fluorophenyI)-6-tetrahydropyran-4-yl-l-(2trimethylsilylethylsulfonyl)pyrrolo[2,3-f]indazol-7-yl]benzoate C68 (73 mg, 0.10 mmol) and CsF (152 mg, 1.0 mmol) were stirred in MeCN (5.0 mL) at 80 °C. The reaction mixture was then concentrated in vacuo and purified by silica gel chromatography (0 - 100 % EtOAc in dichloromethane) to afford the product. (22.8 mg, 31 %). ’H NMR (400 MHz, Methanol-d₄) 5 8.15 (d, J = 7.9 Hz, 2H), 8.03 - 8.00 (m, IH), 7.66 (d, J = 7.9 Hz, 2H), 7.57 - 7.48 (m, 4H), 7.45 7.32 (m, 5H), 6.93 (s, IH), 5.43 (s, 2H), 3.81 - 3.75 (m, 2H), 3.19 (t, J = 11.6 Hz, 2H), 2.99 (t, J = 12.5 Hz, 2H), 1.84- 1.63 (m, 6H). LCMS m/z 564.5 [M+H]⁺.

Step 8. 4-[8-fluoro-5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3-f] indazol- 7yl]benzoic acid (45)

343

A solution of benzyl 4-[8-fluoro-5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lHpyrrolo[2,3-f]indazol-7-yl]benzoate C69 (22 mg, 0.04 mmol) in EtOH (330 pL) and THF (330 pL) was added to a flask containing Pd on carbon catalyst (4.1 mg, 0.04 mmol) under an inert atmosphère. The reaction mixture was subjected to hydrogénation conditions under a balloon 5 pressure atmosphère of H₂ (3.0 mg, 1.5 mmol) for 90 min. The reaction was fïltered through Celite®. The filtrate was purified by reverse phase chromatography (Gradient: 0 - 100 % MeCN in water containing 10 mM ammonium formate) to afford the product (8.2 mg, 40%). ’H NMR (400 MHz, Methanol-i/₄) δ 8.11 (d, J = 7.8 Hz, 2H), 8.01 (d, J = 3.2 Hz, IH), 7.62 (d, J = 7.9 Hz, 2H), 7.58 - 7.51 (m, 2H), 7.42 (t, J = 8.3 Hz, 2H), 6.93 (s, IH), 3.83 - 3.74 (m, 2H), 3.18 10 (t, J = 11.6 Hz, 2H), 3.00 (t, J = 12.3 Hz, IH), 1.84 - 1.72 (m, 2H), 1.70 - 1.63 (m, 2H). LCMS m/z 474.4 [M+H]⁺.

344

Compound 46

4-[5-(4-fluorophenyl)-6-tetrahydropyran-3-yl-lH-pyrrolo[2,3-J]indazol-7-yl]benzoic acid (46)

ΙΟ

Step l. Synthesis of 5-bromo-6-(2-tetrahydropyran-3-ylethynyl)-IH-indazole (C70)

To a solution of 5-bromo-6-îodo-IH-indazole Cl (2.5 g, 7.74 mmol) in DMF (15.6 mL) under a nitrogen atmosphère, was added 3-ethynyltetrahydropyran (852 mg, 7.74 mmol), Et₂NH (2.4 mL, 23.2 mmol), PdCl₂(PPh₃)₂ (275 mg, 0.4 mmoi) and Cul (110 mg, 0.58 mmol). The reaction mixture was heated to 90 °C for 1 h. Water and CH₂C1₂ were added and the organic phase was separated on a phase separator. The organic layer was concentrated in vacuo and purified by silica gel chromatography (Eluent: Ethyl acetate in heptanes) to afford the product (1.32 g, 56%). ¹H NMR (300 MHz, DMSO-rf₆) δ 13.31 (s, IH), 8.13 (s, IH), 8.06 (t, J = 1.2 Hz, IH), 7.69 (s, IH), 3.90 (ddd, J = 10.9, 4.1, 1.3 Hz, IH), 3.78 - 3.68 (m, IH), 3.51 - 3.41 (m, 2H), 2.90 -2.79 (m, IH), 2.12 - 2.01 (m, IH), 1.78- 1.47 (m, 3H). LCMS m/z 305.1 [M+H]⁺.

345

Step 2. Synthesis of N-(4-fluorophenyl)-6-(2-tetrahydropyran-3-ylethynyl)-lH-inàazol-5-amine (C71)

A solution of 5-bromo-6-(2-tetrahydropyran-3-ylethynyl)-lH-indazo!e C70 (l.27 g, 4.16 mmol), 4-fluoroaniline (562 pL, 5.9 mmol) and NaOtBu (709 mg, 7.4 mmol) in tBuOH (20.6 mL) at 40 °C was purged with nitrogen for 10 min. tBuXPhos Pd G3 was added and the mixture was purged with nitrogen for an additional 10 min. The reaction was then heated to 70 °C for l h. Additional 4-fluoroaniline (562 pL, 5.93 mmol), NaOtBu (709 mg, 7.38 mmol) and tBuXPhos Pd G4 (3.3 mg, 0.004 mmol) were added and the reaction stirred for an additional 2 h. One further portion of additional reagents were added, 4-fluoroaniline (562 pL, 5.93 mmol), NaOtBu (709 mg, 7.38 mmol) and tBuXPhos Pd G4 (3.3 mg, 0.004 mmol). The mixture was then heated ovemight. Purification by silica gel chromatography (0 - 100 % EtOAc in heptane) afforded the product (535 mg, 36 %). LCMS m/z 336.3 [M+H]⁺.

Step 3. Synthesis of 5-(4fluorophenyl)-6-tetrahydropyran-3-yl-lH-pyrrolo[2,3-f]indazole (C72)

A solution of N-(4-fluorophenyl)-6-(2-tetrahydropyran-3-ylethynyl)-lH-indazol-5-amine C71 (465 mg, 1.32 mmol) in DMSO (1.8 mL) was heated at 150 °C for 30 min. Water was added and the solid product precipitated out. The solid was filtered and dried to afford the product (345 mg, 66 %). 'H NMR (400 MHz, DMSO-rf₆) δ 12.62 (s, IH), 7.97 (t, J = 1.3 Hz, IH), 7.56 (t, J = 1.1 Hz, IH), 7.48 (t, J = 8.9 Hz, 2H), 7.16 (q, J = 0.8 Hz, IH), 6.54 (s, IH), 3.88 - 3.75 (m, 2H), 3.41 - 3.35 (m, IH), 2.82 -2.72 (m, IH), 2.07- 1.95 (m, IH), 1.81 - 1.69 (m, IH), 1.66- 1.56 (m, IH), 1.55 - 1.42 (m, IH). LCMS m/z 336.3 [M+H]⁺.

Step 4. Synthesis of l-[5f4fluorophenyl)-6-tetrahydropyran-3-yl-pyrrolo[2,3-f]indazol-1 -yl]2,2-dimethyl-propan-1 -one (C73)

A solution of 5-(4-fluorophenyl)-6-tetrahydropyran-3-yl-lH-pyrrolo[2,3-f]indazole C72 (325 mg, 0.97 mmol) în THF (7.3 mL) was cooled to 0 °C in an ice bath. KOtBu (267 pL, 2.15 mmol) was added and the reaction allowed to stir for 5 min. 2,2-Dimethylpropanoyl chloride (463 pL, 3.76 mmol) was then added and the reaction allowed to stir at 0 °C for 1 h. Purification by silica gel chromatography (0 - 100 % EtOAc/dichloromethane) afforded the product (260 mg, 57 %). LCMS m/z 420.4 [M+H] 2

Step 5. Synthesis of l-[5-(4fluorophenyl)-7-iodo-6-tetrahydropyran-3-yl-pyrrolo[2,3f]indazol1 -yl]-2,2-dimethyl-propan-l~one (C74) l-iodopyrrolidine-2,5-dione (174 mg, 0.73 mmol) was added portion-wise over 30 min to a solution of l-[5-(4-fluorophenyl)-6-tetrahydropyran-3-yl-pyrrolo[2,3-f]indazol-l-yl]-2,2dimethyl-propan-I-one C73 (252 mg, 0.60 mmol) in CH₂CI₂ (2.6 mL) at 0 °C. After 1 h, the mixture was washed with IM Na₂SO3. The organic phase was collected through a phase separator to afford the product (300 mg, 87 %). ’H NMR (400 MHz, DMSO-ri₆) δ 8.44 (d, J =

346

0.8 Hz, IH), 8.39 (t, J = 0.9 Hz, IH), 7.66 - 7.57 (m, 2H), 7.56 - 7.50 (m, 2H), 7.29 (d, J = 0.9 Hz, IH), 3.90 - 3.80 (m, 2H), 3.36 - 3.27 (ni, IH), 2.97 - 2.85 (m, IH), 2.43 - 2.30 (ni, IH), 1.93 (d, J = 13.1 Hz, IH), 1.64 (d, J = 13.5 Hz, IH), 1.52 (s, 9H), 1.50 - 1.40 (m, 2H). LCMS m/z 546.4 [M+Hf.

Step 6. Synthesis of ethyl 4-[I-(2,2-dimethylpropanoyl)-5-(4-fluorophenyl)-6-tetrahydropyran-3yl-pyrrolo[2,3-f]indazol-7-yl]benzoate (C75)

A mixture of l-[5-(4-fluorophenyl)-7-iodo-6-tetrahydiOpyran-3-yI-pyrrolo[2,3-f]indazoll-yl]-2,2-dimethyl-propan-l-one C74 (242 mg, 0.42 mmol), (4-ethoxycarbonylphenyl)boronic acid (169 mg, 0.87 mmol) and Pd(dppf)Cl₂ (16.9 mg, 0.021 mmol) was placed în a vial and purged with nitrogen. 1,4-Dioxane (1.4 mL) and sodium carbonate (677 pL of 2 M, 1.35 mmol) were added and the reaction was then stirred at 95 °C for 1 h. Water and CH₂C1₂ were added. The phases were separated on a phase separator. Purification by silica gel chromatography (0 -100 % CH₂Cl₂/heptane) afforded the product (142 mg, 53 %). LCMS m/z 568.5 [M+H] L Step 7. Synthesis of 4-[5-(4-fluorophenyl)-6-tetrahydropyran-3-yl-lH-pyrrolo[2,3-]]indazol-7yl] benzoic acid (46)

NaOH (163 pL of 1 M, 0.16 mmol) was added to a solution of ethyl 4-(1-(2,2dimethylpropanoyl)-5-(4-fluorophenyl)-6-tetrahydropyran-3-yl-pyrrolo[2,3-f[indazol-7yl]benzoate C75 (23 mg, 0.04 mmol) in THF (476 pL) and MeOH (202 pL). The reaction was heated at 50 °C for 30 min. The mixture was concentrated in vacuo, and then re-dissolved in minimal water. HCl (163 pL of 1 M, 0.16 mmol) was added and the mixture fïltered to afford the product (11.6 mg, 70%). ’H NMR (400 MHz, DMSO-<7₆) δ 13.03 (s, IH), 12.60 (s, IH), 8.12 (d, J = 7.5 Hz, 2Η), 8.01 (s, IH), 7.70 - 7.58 (m, 4Η), 7.52 (t, J = 8.5 Hz, 2Η), 7.22 (s, IH), 7.10 (s, IH), 3.87 (d, J = 10.4 Hz, IH), 3.69 (d, J = 10.9 Hz, IH), 3.32 - 3.28 (m, IH), 3.03 - 2.87 (m, 2H), 1.88 (d, J = 12.8 Hz, IH), 1.63 - 1.50 (m, IH), 1.48 - 1.30 (m, 2H). LCMS m/z 455.5 [M+H]⁺.

347

Compound 47 and 48

4-[5-(4-fluorophenyl)-6-tetrahydropyran-3-yl-lH-pyrrolo[2,3-f]indazol-7-yl]benzoic acid [ENANT-1] (47) and 4-]5-(4-fluorophenyl)-6-tetrahydropyran-3-yl-lH-pyrrolo]2,3-f]mdazol-7yl]benzoic acid [ENANT-2] (48)

Racemic 4-[5-(4-fluorophenyl)-6-tetrahydropyran-3-yI-lH-pyrrolo[2,3-f]indazoI-7yl]benzoic acid 46 (54 mg, 0.11 mmol) was separated into its constituent enantiomers 47 and 48 by chiral SFC purification. Column: Daicel Chiralpak AD-H, Mobile phase: 30 % IPA (5 mM 10 Ammonia), 70% CO₂. 4-[5-(4-fluorophenyl)-6-tetrahydropyran-3-yl-lH-pynOlo[2,3-f|indazol7-yl]benzoic acid [ENANT-1] (47) was the first elutîng enantiomer. 4-[5-(4-fluorophenyI)-6tetrahydiOpyran-3-yl-lH-pynOlo[2,3-f]indazol-7-yl]benzoic acid [ENANT-2] (48) was the second eluting enantiomer. Both compounds were further purified by reverse phase chromatography (10-100 % MeCN in water containing 0.1 % formic acid) to afford the products.

4-[5-(4-fluorophenyl)-6-tetrahydropyran-3-yl-lH-pyrrolo[2,3-f]Îndazol-7-yl]benzoic acid [ENANT-1] (47) (13 mg, 27 %). NMR (400 MHz, DMSO-riQ δ 13.01 (s, IH), 12.60 (s, IH), 8.17 - 8.08 (m, 2H), 8.01 (s, IH), 7.69 - 7.58 (m, 4H), 7.52 (t, J = 8.5 Hz, 2H), 7.22 (s, IH), 7.10 (s, IH), 3.91 - 3.84 (m, IH), 3.69 (d, J = 11.2 Hz, IH), 3.32 - 3.27 (m, IH), 2.95 (q, J = 11.7 Hz, 2H), 1.89 (d, J = 12.4 Hz, IH), 1.63 - 1.50 (m, IH), 1.48 - 1.29 (m, 2H). LCMS m/z 456.3 20 [M+H]⁺.

4-[5-(4-fluorophenyl)-6-tetrahydropyran-3-yl-lH-pynOlo[2,3-f]indazol-7-yI]benzoic acid [ENANT-2] (48) (13.9 mg, 26 %). 'H NMR (300 MHz, DMSO-^) δ 12.59 (s, IH), 8.11 (d, J = 8.1 Hz, 2H), 8.00 (s, IH), 7.69 - 7.58 (m, 4H), 7.56 - 7.47 (m, 2H), 7.22 (s, IH), 7.10 (s, IH), 3.92 - 3.81 (m, IH), 3.73 - 3.65 (m, IH), 3.27 (s, IH), 3.03 - 2.88 (m, 2H), 1.94 - 1.84 (m, IH), 25 1.66 - 1.50 (m, 1 H), 1.48 - 1.29 (m, 2H). LCMS m/z 456.1 [M+H]⁺.

348

Compound 49

Synthesis of 4-[5f4-fluorophenyï)-6-isopropyl-1 H-pyrrolo[2,3-f] indazol-7-yl]-3-methoxybenzoic acid (49)

Step 1. 4-[l-(2,2-dimethylpropanoyl)-5-(4-fluorophenyl)-6-isopropyl-pyrrolo[2,3-fJindazol-7yl]-3-methoxy-benzoate (C76)

To a solution of l-[5-(4-fluorophenyI)-7-iodo-6-isopropyl-pyrrolo[2,3-f]indazo1-l-yl]2,2-dimethyl-propan-l-one S7 (4.90 g, 9.50 mmol), methyl 3-methoxy-4-(4,4,5,5-tetramethyl10 l,3,2-dioxaborolan-2-yl)benzoate (5.11 g, 17.5 mmol), and Pd(dppf)Cl₂ (604mg, 0.74 mmol) in 1,4-dioxane (43 mL) was added sodium carbonate (17 mL ot 2 M, 34 mmol). The reaction mixture was purged with nitrogen and the solution was stirred at 90 °C for 90 min. Water (100 mL) and dîchloromethane (100 mL) were added and the mixture was extracted with dîchloromethane (3 x 100 mL). The organic layers were combined, passed through a phase 15 separator and concentrated in vacuo. Purification by silica gel column chromatography (Eluent: 0-100 % dîchloromethane in heptane). To a solution of pure material in dîchloromethane (150 mL) was added ΜΡ-ΤΜΊ palladium scavenging resin (3.09 g). The suspension was stirred ovemight at room température. The mixture was fïltered, washed with dîchloromethane, and concentrated in vacuo to afford the product (2.98 g, 58 %). LCMS m/z 542.5 [M+H]⁺.

349

Step 2. Synthesis of4-[5-(4-Jluorophenyl)-6-isopropyl-lH-pynOlo[2,3-f]indazol-7-yl]-3methoxy-benzoic acid (49)

To a solution of methyl 4-[l-(2,2-dimethylpropanoyl)-5-(4-fluorophenyl)-6-isopropylpyrrolo[2,3-f]indazol-7-yl]-3-methoxy-benzoate C76 (1.2 g, 2.15 mmol) in THF (24 mL) and 5 MeOH (12 mL) was added NaOH (12.84 mL of 1 M, 12.84 mmol). The solution was stirred at 50 °C for 1 h. The solvent was evaporated and the crude materiai was taken up in minimal water. HCl (12.8 mL of 1 M, 12.8 mmol) was added, forming a precipitate. Minimal DMSO was added to the suspension. Purification by reverse phase column chromatography (Eluent: 10-100% acetonitrile in water with 0.2 % fonnic acid modifier) afforded the desired product (1.29 g, 10 66 %). ^lH NMR (400 MHz, DMSO-^) δ 13.04 (s, IH), 12.51 (s, IH), 7.97 (s, IH), 7.71 - 7.66 (m, 2H), 7.64 - 7.56 (m, 2H), 7.52 - 7.42 (m, 3H), 7.06 (s, IH), 6.99 (s, IH), 3.80 (s, 3H), 2.99 (hept, J = 7.6, 6.9 Hz, IH), 1.08 (d, J = 6.9 Hz, 3H), 1.01 (d, J = 6.8 Hz, 3H). LCMS m/z 444.4 [M+H]’.

Compound 50

3-chloro-4-[5-(4-fluorophenyl)-6-isopropyl-lH-pyrrolo[2,3-f] indazol- 7-yl]benzoic acid (50)

Step 1.Synthesis of methyl 3-chloro-4-[l-(2,2-dimethylpropanoyl)-5-(4-Jluorophenyl)-6isopropyl-pyrrolof2,3-f] indazol- 7-yl] benzoate (C77)

-[5-(4-fluorophenyl)-7-iodo-6-isopropyl-pyrrolo[2,3-f] indazol- l-yl]-2,2-dimethyl20 propan-I-one (50 mg, 0.10 mmol) S7, XPhos Pd G4 (84 mg, 0.1 mmol), (2-chloio-4methoxycarbonyl-phenyl)boronic acid (23 mg, 0.11 mmol) and K3PO4 (61 mg, 0.3 mmol) were dissolved in 1,4-dioxane (300 pL) and water (30 pL). The mixture was purged with nitrogen, 350 and the solution was stirred at 85 °C for l h. Water and dichloromethane were added and the solution was passed through a phase separator. The organic layer was concentrated in vacuo. Purification by silica gel column chromatography (Eluent: 0-80 % dichloromethane in heptane) afforded the product (l 8 mg, 23 %). LCMS m/z 545.2 [M+H]⁺.

Step 2. Synthesis of 3-chloro-4-[5-(4-fluorophenyl)-6-isopropyl-lH-pyrrolo[2,3-f]indazol-7yl]benzoic acid (50)

To a solution of 3-chloro-4-[ 1-(2,2-dimethylpropanoyl)-5-(4-fluorophenyl)-6-isopropylpyrrolo[2,3-f]indazol-7-yl]benzoate C77 (52 mg, 0.03 mmol) and piperidine (18.1 pL, 0.18 mmol) (12 mL) in THF (1.0 mL) and MeOH (521 pL), was added NaOH (12.8 mL of 1 M, 12.8 mmol). The solution was stirred at 50 °C for 1 h. The solvent was evaporated and the crude reaction mixture was dissolved in minimal water. HCl (12.8 mL of I M, 12.8 mmol) were added, forming a precipitate. Dichloromethane was added and the organic layer was collected using a phase separator. Purification by reverse phase column chromatography (Eluent: MeCN in water with 0.1 % Formic acid modifier) afforded the desired product (24 mg, 62 %). *H NMR (400 MHz, DMSO-40 Ô 13.39 (s, IH), 12.54 (s, IH), 8.16 - 8.11 (m, IH), 8.03 - 7.97 (m, 2H), 7.66 (d, J = 7.8 Hz, IH), 7.64 - 7.55 (m, 2H), 7.54 - 7.45 (m, 2H), 7.12 (s, IH), 6.92 (s, IH), 2.96 (p, J = 7.1 Hz, IH), 1.11 (d, J = 7.0 Hz, 3H), 0.99 (d, J = 7.0 Hz, 3H). LCMS m/z 448.3 [M+H]⁺.

Compound 51

3,5-difluoro-4-[5-(4-fluorophenyl)-6-isopropyl-lH-pyrrolo[2,3-flindazol-7-yl]benzoic acid (51)

351

Step 1. Synthesis of methyl 4-[l-(2,2~dimethylpropanoyl)-5-(4-Jluorophenyl)-6-isopropylpyrrolo[2,3-f] indazol- 7-yl]-3,5-difluoro-benzoate (C79)

Part A. Préparation of organozinc reagent (C78): To a solution of CoBr₂ (15 mg, 0.07 mmol), ZnBr_z (40 mg, 0.18 mmol), and Zn (189 mg, 2.90 mmol) acetonitrîle (1000 pL) under nitrogen was added bromobenzene (7 pL, 0.07 mmol) and TFA (2.5 pL, 0.03 mmol). The resulting solution was stirred for 1 h then methyl 4-bromo-3,5-difluoro-benzoate (146 mg, 0.6 mmol) was added. The solution was stirred for an additional 48 h. The reaction was filtered and the supernatant was used immediately in part B of the reaction.

Part B. Coupling of organozinc reagent and S7: The supernatant from part A (C78) was transferred to a flask and degassed for 5 min. l-[5-(4-fluorophenyl)-7-iodo-6-îsopropylpyrrolo [2,3-f] indazol- 1-yl]-2,2-dimethyl-propan-l-one (76 mg, 0.15 mmol) (S7) and Pd(PPh₃)₄ (20 mg, 0.02 mmol) were added and the solution was stirred at 50 °C ovemight. Solvent was removed in vacuo. Purification by silica gel column chromatography (Eluent: 0-10% ethyl acetate in heptane) afforded the product (8 mg, 9 %). ’H NMR (400 MHz, Chloroform-d) δ 8.17 (s, IH), 7.98 (s, JH), 7.65 (d, J = 6.6 Hz, 2H), 7.39 (dd, J = 7.4, 5.2 Hz, 2H), 7.23 (t, J = 7.9 Hz, 2H), 7.07 (s, IH), 3.96 - 3.92 (m, 3H), 3.01 - 2.90 (m, IH), 1.46 (s, 9H), 1.10 - 1.00 (m, 6H). LCMS m/z 548.5 [M+H] ^h.

Step 2. 3,5-difluoro-4-[5-(4-fluorophenyl)-6-isopropyl-ÎH-pyrrolo[2,3-f] indazol- 7-yl]benzoic acid (SI)

Compound 51 was prepared from C79 by saponification using NaOH as described in the préparation of compound 49 step 2. ^!H NMR (400 MHz, Chloroform-d) δ 7.99 (s, IH), 7.74 (d, J - 7.0 Hz, 2H), 7.63 - 7.48 (m, 2H), 7.40 (t, J = 8.2 Hz, 2H), 7.16 (d, J = 2.0 Hz, IH), 7.10 (s, IH), 3.12-3.01 (m, IH), 1.13 (d, J = 6.6 Hz, 6H). LCMS m/z 450.4 [M+H].

352

Compound 52

5-[5-(4-fluorophenyl)-6-isopropyl-lH-pyrrolo[2,3-f] indazol-7-y l]-3-methyl-pyridine-2carboxylic acid (52)

Synthesis of 5-[5-(4-fluorophenyl)-6-isopropyl-l H-pyrrolo[2,3-f] indazol-7-yl]-3-methylpyridine-2-carboxylic acid (52)

A solution of l-[5-(4-fluorophenyl)-7-iodo-6-isopropyl-pyrrolo[2,3-f]nidazol-l-yl]-2,2dimethyl-propan-l-one (81 mg, 0.2 mmol) (S7), methyl 3-methyl-5-(4,4,5,5-tetramethyM,3,2dioxaborolan-2-yl)pyndine-2-carboxylate (87 mg, 0.30 mmol), Cs₂CO₃ (95 mg, 0.30 mmol), 10 dppf (16 mg, 0.030 mmol), Pd(OAc)₂ (3 mg, 0.02 mmol), and CuCI (43 mg, 0.4 mmol) in DMF (1.6 mL) was purged with nitrogen for 10 min, then heated at 100 °C for 45 min. NaOH (965 pL of 1 M, 0.97 mmol) was added and the reaction was stirred for 30 min. Water (5 mL) and dichloromethane (5 mL) were added. The organic layer was collected and filtered through a Celite® plug, and washed with excess dichloromethane to afford the product (2 mg, 3 %). H 15 NMR (400 MHz, Methanol-^) Ô 8.67 (s, IH), 8.23 (s, IH), 8.03 (s, IH), 7.58 - 7.50 (m, 2H), 7.45 - 7.39 (m, 3H), 7.16 (s, IH), 3.26 - 3.20 (m, IH), 2.82 (s, 3H), 1.21 (d, J = 7.0 Hz, 6H). LCMS m/z 429.4 [M+H]\

353

Compounds 53-65

Compounds 53-67 (see Table 6) were prepared in two steps from intermediate S7 and the appropriate boronic acid or ester reagent, using the cross coupling and saponification methods as described for compounds 49-51. Modifications to these methods are noted in Table 6 and 5 accompanying footnotes.

Table 6. Method of préparation, structure, physicochemical data for compounds 53-65

Compound	Meth od/Product	Boronic acid or ester	NMR; LCMS m/z [M+H]'
53	Compound 491 from S7 F-OH H n Ύ L /—\ F	MeO^O 4 HO' ΌΗ	'HNMR (400 MHz, DMSO-JJÔ 13.32 (s, IH), 12.58 (s, IH), 8.00 (s, IH), 7.93 (d, J = 7.9 Hz, IH), 7.86 (d, J = 10.1 Hz, IH), 7.67 (dd, J = 16.0,8.4 Hz, 3H), 7.50 (t, J = 8.5 Hz, 2H), 7.10 (s, 2H), 3.04 (q, J = 7.1 Hz, IH), 1.09 (dd, J = 22.3, 7.1 Hz, 5H). LCMS m/z 430.7 [M+Hf.
54	Compound 492 from S7 JVoH O H / n. Ύ [Vf N X À F	ho.doh LJ 0 O^OEt	’HNMR (300 MHz, DMSO-^S 12.90 (s, IH), 12.67 (s, IH), 8.18-8.04 (m,2H), 8.00 (d, J = 1.0 Hz, IH), 7.71 - 7.55 (m, 4H), 7.50 (t, J = 8.7 Hz, 2H), 7.31 (t, J = 1.1 Hz, IH), 7.06 (d. J = 1.1 Hz, 1H),3.18 (p, J = 7.1 Hz, IH), 1.13 (d, J = 7.2 Hz, 6H). LCMS m/z 414.2 [M+H]’.

354

Compound	Method/Product	Boronic acid or ester	lH NMR; LCMS m/z [M+H]+
55	Compound 49 from S7 CL y-OH Fa N OMe n.x ιΓΜ F	MeO^O X y^OMe G	'H NMR (400 MHz, DMSOA) δ 13.01 (s, IH), 12.55 (s, IH), 7.99 (s, IH), 7.93 (d, J = 7.4 Hz, IH), 7.83 (d, J = 7.4 Hz, IH), 7.67-7.61 (m, IH), 7.61-7.54 (m, IH), 7.53 - 7.45 (m, 2H), 7.08 (s, IH), 7.04 (s, IH), 3.93 - 3.89 (m, 3H), 2.99 (dq, J = 14.4,6.8 Hz, IH), 1.08 (d, J = 7.0 Hz, 3H), 1.02 (d, J = 7.0 Hz, 3H). LCMS m/z 445.4 [M+H]+.
56	Compound 49 from S7 JV0H NCW H / F	O^OMe jO NC^V	'HNMR (400 MHz, DMSOA) δ 13.59 (s, IH), 12.62 (s, IH), 8.47 (s, IH), 8.34 (d, J = 7.9 Hz, IH), 8.03 (s, 1 H), 7.82 (d, J = 8.1 Hz, IH), 7.67 - 7.56 (m, 2H), 7.52 (t, J = 8.7 Hz, 2H),7.15(s, IH), 7.06 (s, IH), 3.04 (p, J = 7.I Hz, IH), 1.12 (d, J = 7.0 Hz, 3H), 1.04 (d, J = 7.0 Hz, 3H). LCMS m/z 439.3 [M+H]+,
57	Compound 493 from S7 a 0 OH H / NAVÎ / νΙΓΗ n x F	OH Γ || CJri MeCTO	'H NMR (400 MHz, Methanol-ift) δ 8.07 (s, IH), 8.02 (s, IH), 7.98 (s, IH), 7.72 (s, IH), 7.56- 7.52 (m, 2H), 7.40 (t, J = 8.2 Hz, 2H), 7.32 (s, IH), 7.12 (s, IH), 3.21 3.15 (m, IH), 1.18 (d, J = 7.0 Hz, 6H). LCMS m/z 448.3 —

355

Compound	Method/Product	Boronic acid or ester	’HNMR; LCMS m/z [M+Hf
			[M+H]‘.
58	Compound 491 from S7 s0 H / / Q F	P ho-b OH	'H NMR (400 MHz. DMSO-76)ô 13.08 (s, IH), 12.67 (s, IH), 8.02 (s, IH), 7.84 (d, J = 3.9 Hz, IH), 7.67 7.61 (m,2H), 7.537.47 (m,3H), 7.25 (d, J = 3.7 Hz, IH), 7.07 (s, 11-1),3.30-3.23 (m, IH), 1.18 (d, J = 7.1 Hz, 6H). LCMS m/z 420.3 [M+H]+.
	Compound 491 from S7
59	H N-x^ <1	V-OH O Ύη ô	OEt 3 OH	lH NMR (400 MHz, Methanol-d4) δ 7.95 (s, IH), 7.52 - 7.42 (m, 4H), 7.42 - 7.30 (m, 5H), 7.07 (s, IH), 3.70 (s, 2H), 3.243.10 (m,lH), 1.15 (d, J = 7.1 Hz, 6H). LCMS m/z 428.4 [M+Hf.
		F

356

Compound	Method/Product	Boronic acid or ester	’H NMR; LCMS m/z [M+H]’
60	Compound 49 from S7 OH MeO / O H / F	MeO^.0 MeO^X | J O O	‘H NMR (400 MHz, Methanol-iL) δ 8.01 7.94 (m, 2H), 7.55 7.48 (m, 2H), 7.42 7.36 (m, 3H), 7.25 (s, IH), 7.19 (d, J = 8.0 Hz, IH), 7.10 (s, IH), 3.96 (s, 3H), 3.28 3.18 (m, IH), 1.21 (d, J = 7.1 Hz, 6H). LCMS m/z 444.3 [M+1I]+.
61	Compound 491,4 from S7 F 3C 0 γ/θΗ H / \XjCW 0 F	OMe F3C^Ç A 0 0	’HNMR (400 MHz, DMSO-î/6)ô 13.69 (s, IH), 12.60 (s, IH), 8.32 (s, IH), 8.22 (s, IH), 8.06 (s, IH), 8.01 (s, IH), 7.67 7.60 (m, 2H), 7.567.47 (m, 2H), 7.29 (s, IH), 7.10 (s, IH), 3.12 (p, J = 7.0 Hz, IH), 1.13 (d, J = 7.1 Hz, 6H). LCMS m/z 482.3 [M+H]+.
62	Compound 50 from S7 O OH H / / Nccxyx F	HO.^OH Ct ΚΛγΟ OMe	‘H NMR (400 MHz, DMSO-rf6)Ô 12.52 (s, IH), 8.05 - 7.98 (m, 3H), 7.77 (d, J = 8.2 Hz, IH), 7.68 - 7.56 (m, 2H), 7.53 - 7.45 (m, 2H), 7.13 (s, IH), 6.92 (s, IH), 2.95 (p, J = 7.0 Hz, IH), 1.11 (d, J = 7.0 Hz, 3H), 0.99 (d, J = 7.0 Hz, 3H). LCMS m/z 448.3 [M+H]’.

357

Compound	Method/Product	Boronic acid or ester	’H NMR; LCMS m/z [M+H]1
63	Compound 495 from S7 O \ U Νχ^ΟΗ M H / NX )O\ F	O i /	'H NMR (400 MHz, DMSO-46) δ 13.48 (s, IH), 12.60 (s, IH), 7.98 (s, IH), 7.66 (s, IH), 7.61 - 7.55 (m, 2H), 7.49 (t, J = 8.5 Hz, 2H), 7.02 (s, IH), 6.96 (s, IH), 4.20 (d, J = 1.5 Hz, 3H), 3.293.25 (m, IH), 1.20 (d, J = 7.0 Hz, 6H). LCMS m/z 418.3 [M+H]+.
64	Compound 521 from S7 OH oX. 4 v V-N H Γ vCjCm F	MeO^.O J zÇ°	‘H NMR (400 MHz, Methanofp) δ 8.85 (d, J = 5.0 Ηζ,ΙΗ), 8.17 (s, IH), 7.99 (s, IH), 7.89 (d, J = 5.1 Hz, IH), 7.58 - 7.50 (m, 3H), 7.40 (t, J = 8.3 Hz, 2H), 7.13 (s, IH), 3.34 (IH obscured by solvent peak), 1.20 (d, J = 7.0 Hz, 6H). LCMS m/z 415.2 [M+H]+.
65	Compound 496 from S7 O ΗθΧ /X XyNH H / N-^aU. / xX JA\ F	ü 1 NH MeO j| η ,BX JD__CJ	*H NMR (400 MHz, Methanol-44) δ 8.00 7.94 (m, 2H), 7.75 (s, IH), 7.52 (dd, J = 8.3, 4.9 Hz, 2H), 7.46 (d, J = 3.1 Hz, lH),7.38(t, J = 8.4 Hz, 2H), 7.14 (d, J = 3.0 Hz, IH), 7.11 (s, IH), 3.18(dq, J =15.7, 8.3, 7.6 Hz, IH), 1.17 (d, J = 7.1 Hz, 6H). LCMS m/z 453.5 [M+Hf.

’· Purification by reversed-phase HPLC. Method: CI8 Waters Sunfire column (30 xl50 mm, 5 micron). Gradient: 10-100 % MeCN in H₂O with 0.2 % formic acid. Compounds 53,58, 59,61,64.

358 ^:· Compound 54 precîpitated upon neutralization with HCL The product was filtered, washed with water, precîpitated in ethyl acetate and dried in vacuo. Then washed with IN HCl, dried with sodium sulfate, filtered and dried in vacuo. Product was then stirred in NaOH (0.5 M), diluted with water and extracted with ethyl acetate. Dried in vacuo and 5 in the oven ovemight at 50 °C to afford product.

Compound 57: Purification of step 1 by reversed-phase HPLC. Method: Cl 8 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: 10-100 % MeCN in H₂O.

⁴· Compound 61: Purification by silica gel column chromatography (Gradient: 0-80 % dichloromethane in heptane) afforded the product in step 1.

⁵‘ Compound 63: Purification by reversed-phase chromatography on a C1 8 column.

Gradient: 10-100 % MeCN in H₂O with 0.1 % trifluoroacetic acid.

⁶' Compound 65: Purification by reversed-phase chromatography on a C18 column. Gradient: 10-100 % MeCN in H₂O with 0.2 % fonnic acid.

359

Compound 66 (2S, 3S, 4S, 5R)-6-[4-[5-(4-fluorophenyl)-6-isopropyl-1 H-pyrrolo[2,3-J] indazol- 7-yl] bcnzoyl] oxy3,4,5-trihydroxy-tetrahydropyran-2-carboxylic acid (66)

⁵⁴ C82

Step l. allyl (2 S, 3S, 4S, 5R)-6-[4-[5-(4-fiuorophenyl)-6-isopropyl-lH-pyrrolo[2,3-flindazol- 7yl] benzoyl]oxy-3,4,5-trihydroxy-tetrahydropyran-2-carboxylate (C82)

To a solution of 4-[5-(4-fluorophenyl)-6-isopiOpyl-lH-pyrroio[2,3-f]indazol-7yl]benzoic acid (54) (368.6 mg, 0.89 mmol), allyl (2S,3S,4S,5R)-3,4,5,6tetrahydroxytetrahydropyran-2-carboxyIate C81 (209 mg, 0.89 mmol), and HATU (338 mg, 10 0.89 mmol) in MeCN (10 mL) was added NMM (196 pL, 1.78 mmol). The solution was stirred ovemight. THF (9 mL) was then added and the solution was stirred for 4 h then N-methy]

360 pyrrolidone (3 mL) was added. The solution was stirred ovemight and then further NMM (196 pL, L8 mmol) was added. The solvent was removed in vacuo followed by purification by silica gel column chromatography (Eluent: 0-10 % methanol în dichloromethane) to afford the product (157 mg, 27 %). LCMS m/z 630.5 [M+Hf.

Step 2.(2S,3S,4S,5R)-6-[4-[5-(4-(ΙαοηορΗβηγΙ)-6-ί3ορΓοργΙ-1Η-ργηηοΙο[2,3-îj indazol-7yl] benzoyl]oxy-3,4,5-trihydroxy-tetrahydropyran-2-carboxylic acid (66)

To a solution of allyl (2S,3S,4S,5R)-6-[4-[5-(4-fluorophenyl)-6-isopropyl-lHpyrrolo[2,3-f]indazol-7-yl]benzoyl]oxy-3,4,5-trihydroxy-tetrahydropyran-2-carboxylate C82 (155 mg, 0.24 mmol) in CH2CI2 (20 mL) was added morpholine (44 pL, 0.50 mmol). The 10 mixture was purged with nitrogen for 10 min, and Pd(PPh₃)₄ (9 mg, 0.008 mmol) was added.

After 30 min stirring at room température, MP-TMT palladium scavenging resin was added. The solution was stirred for 4 h, filtered and purified b y reverse phase column chromatography (Eluent: 10-100 % acetonitrîle in water with formic acid modifier) to afford the product (21.3 mg, 15 %). ‘H NMR (300 MHz, DMSO-<7₆) δ 13.04-12.68 (bs, IH), 12.58 (s, IH), 8.23 - 8.14 15 (m, 2H), 7.99 (d, J = 1.0 Hz, IH), 7.74 - 7.67 (m, 2H), 7.65 - 7.57 (m, 2H), 7.49 (t, J = 8.7 Hz,

2H), 7.31 (t, J = 1.1 Hz, IH), 7.06 (d, J = 1.1 Hz, IH), 5.68 (d, J = 7.4 Hz, IH), 5.54 (d, J = 4.2

Hz, IH), 5.30 (d, J = 4.0 Hz, IH), 3.88 (d, J = 8.9 Hz, IH), 3.50 - 3.36 (m, 3H), 3.22 - 3.12 (m,

IH), 1.13 (dd, J = 7.2, 2.1 Hz, 6H). LCMS m/z 590.5 [M+H]⁺.

Compound 67

4-[5-(4-fluorophenyl)-6-isopropyl-1 H-pyrrolo[2,3-j] indazol- 7-yl]-3-(oxetan-3-yloxy)benzoic acid (67)

361

Step 1. methyl 4-[l-(2,2-dimethylpropanoyl)-5-(4-fluorophenyl)-6-isopropyl-pyrrolo[2,3f] indazol-7-yl] -3-(oxetan-3-yloxy)benzoate (C83)

A solution of l-[5-(4-fluorophenyl)-6-isopropyl-7-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)pyrrolo[2,3-f] indazol-l-yl]-2,2-dimethyl-propan-l-one S8 (320 mg, 0.64 mmol), Pd(dppt)C17 (49.1 mg, 0.06 mmol), sodium carbonate (953 pL of 2 M, 1.9 mmol) and methyl 4-bromo-3-(oxetan-3-yloxy)benzoate (182 mg, 0.64 mmol) in 1,4-dioxane (1.9 mL) was stirred at 95 °C for 90 min. Water and dîchloromethane (1:1) were added, and the mixture passed through a phase separator and concentrated in vacuo. Purification by silica gel column chromatography (Eluent: 0-100% EtOAc in heptane) afforded the product (202 mg, 47%). LCMS m/z 584.5 [M+H]⁺.

Step 2. 4-[5-(4-fluorophenyl)-6-isopropyl-lH-pyrrolo[2.3-f]indazol-7-yl]-3-(oxetan-3yloxy)benzoic acid (67)

To a solution of methyl 4-[l-(2,2-dimethylpropanoyl)-5-(4-fluorophenyl)-6-isopropylpynOlo[2,3-f]indazol-7-yl]-3-(oxetan-3-yloxy)benzoate C83 (10 mg, 0.02 mmol) in THF (207 pL) and MeOH (87 pL) was added NaOH (69.3 pL of 1 M, 0.07 mmol). The mixture was stirred at 50 °C for 30 min. Solvent was removed in vacuo and the crude was dissolved in minimal water. HCl was added (69.3 pL of 1 M, 0.07 mmol) and the reaction mixture filtered to afford the product (7.0 mg, 91 %). 'H NMR (400 MHz, DMSO-J₆) δ 13.12 (s, IH), 12.53 (s, IH), 7.98 (s, IH), 7.73 (d, J = 7.7 Hz, 1 H), 7.67 - 7.57 (m, 2H), 7.55 - 7.46 (m, 3H), 7.23 (s, IH), 7.06 (s, 2H), 5.43 - 5.35 (m, IH), 4.86 (dt, J = 19.5, 6.7 Hz, 2H), 4.49 - 4.37 (m, 2H), 3.05 (p, J = 7.2 Hz, 1 H), 1.08 (t, J = 7.7 Hz, 6H). LCMS m/z 586.4 [M+H] λ

Compounds 68-96

Compounds 68-95 (see Table 7) were prepared in a single step from intermediate S8 using the approprîate aryl halide reagent, and using the Suzuki and saponification methods as described for compound 67. Modifications to method are noted in Table 7 and accompanying footnotes.

362

Table 7. Method of préparation, structure, physicochemical data for compounds 68-96

Compound	Method/Product	Aryl H alide	‘H NMR; LCMS m/z [M+H]
68	Compound 674 from S8 O OH H /F n . Ύ XVx jJ F	0^0 Me X^F ( X	'HNMR (400 MHz, DMSO-i/6)Ô 13.34 (s, IH), 12.55 (s, IH), 8.00 (s, IH), 7.94 (t, J = 7.3 Hz, IH), 7.72 (t,J = 7.l Hz, IH), 7.68 -7.57 (m, 2H), 7.50 (t, J = 8.5 Hz, 2H), 7.44 (t, J = 7.5 Hz, !H),7.lO(s, IH), 7.05 (s, IH), 3.01 (p, J =7.1 Hz, IH), 1.10 (d, J = 7.1 Hz, 3H), 1.05 (d, J = 7.0 Hz, 3H). LCMS m/z 432.3 [M+H]+.
69	Compound 674 from S8 oj ° OH H n X £ /—\ F	''X XJ O’ OMe	‘H NMR (400 MHz, DMSO-(/6)Ô 13.10 (s, IH), 12.56 (s, IH), 7.99 (s, IH), 7.66 - 7.59 (m, 3H), 7.53 - 7.47 (m, 2H), 7.45 (s, IH), 7.27 (s, IH), 7.25 - 7.21 (m, IH), 7.06 (s, 1 H), 4.74 (p, J = 6.1 Hz, IH), 3.14 (p, J = 7.1 Hz, IH), 1.34 (d, J = 5.9, 1.4 Hz, 6H), 1.13 (d, J = 7.1 Hz, 6H). LCMS m/z 472.4 [M+H]+.
70	Compound 67l from S8 Cl· y-OH XJ) H / nXaW F	O^^OMe A Br	'HNMR (400 MHz, Methanol-rf4) 5 8.06 (s, IH), 7.98-7.90 (m, 2H), 7.56 - 7.48 (m, 2H), 7.45 (d, J = 7.8 Hz, IH), 7.38 (t,J = 8.5 Hz, 2H), 7.16 (s, lH),6.97(s, IH), 3.00 (hept, J = 6.7, 6.0 Hz, IH), 2.65 (impurity), 2.23 (s,3H), 1.17 (dd, J = 7.2, 1.4 Hz, 3H), 1.02 (dd, J = 7.1, 1.4 Hz, 3H). LCMS m/z 428.6 [M+H]'.

363

Compound	Method/Product	Aryl Halide	lH NMR; LCMS m/z [M+H]'
71	Compound 671,2’3 from S8 0 HoA_ -O H / NaA-a / naXa fl F	0 Br	'H NMR (400 MHz, Methanol-cZj) δ 7.96 (s, IH), 7.92 - 7.85 (m, IH), 7.56-7.47 (m, 3H), 7.42 - 7.34 (m, 3H),7.I5(s, 1 H), 6.97 (s, 1 H), 2.99 (dq, J = 15.4, 7.6 Hz, 1 H), 2.37 (s, 3H), 1.15 (d, J = 7.0 Hz, 3H), 1.02 (d, J = 7.1 Hz, 3H). LCMS m/z 428.3 [M+H]\
72	Compound 673,4,21 from S8 0.. AOH M H Π/\ N y ΓΗ 0Me —AA'' n \ F	O^OMe ÎÙ VA Br OMe	lHNMR (400 MHz, DMSOAQÔ 13.06 (s, IH), 12.51 (s, IH), 7.97 (s, IH), 7.68 (d,J = 7.1 Hz, 2H), 7.63 - 7.44 (m, 5H), 7.04 (s, IH), 7.01 (s, IH), 4.22 -4.08 (m, 2H), 3.55 - 3.43 (m,2H), 3.09 -2.96 (m, 4H), 1.05 (dd, J = 14.7, 7.0 Hz, 6H).LCMS wz 488.5 [M+H]1.
73	Compound 676from S8 OMe W ° oh H NA+A / aA>A-n ' F	O^OMe MeOs^X	‘H NMR (400 MHz, DMSOAQÔ 12.94 (s, IH), 12.55 (s, IH), 7.98 (s, IH), 7.64- 7.56 (m, 3H), 7.54- 7.45 (m, 3H), 7.25 (s, IH), 7.04 (s, IH), 3.84 (s, 3H), 3.12 (p, J = 7.2 Hz, IH), 2.36 (s, 3H), 1.12 (d, J = 7.0 Hz, 6H). LCMS m/z [M+H] 458.4.

364

Compound	Metho d/Produ et	Aryl Halide	’H NMR; LCMS m/z [M+H]+
74	Compound 6712 from S8 O _F~oh H FF FT 1 £ ' F	MeO^O Fn L If Br	‘H NMR (400 MHz, DMSO-ίΑ) δ 13.14 (s, IH), 12.57 (s, IH), 8.02 (d, J = 6.8 Hz, 2H), 7.91 (d, J = 7.8 Hz, IH), 7.68 -7.60 (m, 2H), 7.567.46 (m, 2H), 7.16 (s, IH), 6.90 (s, 1 H), 2.93 (hept, J = 8.9, 8.2 Hz, IH), 2.40 (s,3H), 1.10 (d, J = 7.0 Hz, 3H), 0.95 (d, J = 7.1 Hz, 3H). LCMS m/z 429.4 [M+H]'.
75	Compound 677,8 from S8 V°H QF H / \\X KF—\ F	MeO^O oF JF - Q^y Br	’H NMR (400 MHz, DMSO-</É) δ 12.52 (s, IH), 7.97 (s, IH), 7.69 (d, J = 7.7 Hz, IH), 7.65 (d, J = 4.8 Hz, IH), 7.627.53 (m, 2H), 7.52 - 7.45 (m, 3H), 7.04 (d, J = 4.6 Hz, IH), 7.00 (d, J = 8.9 Hz, IH), 5.14-5.04 (m, IH), 3.87 - 3.77 (m, IH), 3.64- 3.49 (m, 3H), 3.07 -2.96 (m, IH), 2.22 2.03 (m, 2H), 1.88 - 1.74 (m, IH), 1.12-0.99 (m, 6H).LCMS m/z 500.4 [M+H]+.
76	Compound 671 from S8 0 MeoF\F 0H H / N^xF / F [ W 0 F	MeO^O .4 OMe	‘H NMR (400 MHz, MeOD) δ 7.88 - 7.78 (m, 2H), 7.65 (s, IH), 7.247.14 (m,2H), 7.01 (t,J = 8.3 Hz, 2H), 6.88-6.80 (m, 3H), 3.56 (s, 3H), 2.74 (dq, J= 14.0,7.1 Hz, IH), 0.83 (d,J= 7.1 Hz, 3H), 0.76 (d, J=1A Hz, 3H). LCMS m/z 444.3 [M+Hf. -

365

Compound	Method/Product	Aryl Halide	Ή NMR; LCMS m/z [M+H]
77	Compound 673’9 from S8 y0H Ay °Me x 0 F	MeO^O Ό MeO y Br	‘H NMR (400 MHz, DMSO-d6) δ 13.17 (s, IH), 12.56 (s, l H), 7.99 (s, IH), 7.68 (t, J = 7.6 Hz, IH), 7.61 (dd, J = 8.1,5.0 Hz, 2H), 7.50 (t, J = 8.4 Hz, 2H), 7.29 (d, J = 8.1 Hz, IH), 7.11 (s, IH), 7.07 (s, IH), 3.59 (s, 3H), 3.04 (hept, J = 7.5 Hz, IH), 1.08 (dd, J = 11.4, 7.1 Hz, 6H).LCMS m/z 462.4 [M+H]'.
78	Compound 678 from S8 OMe τ' O VJ/ OH H / n X XVa F	O^OMe MeO^/L IV ^ Br	'H NMR (400 MHz, DMSOA) δ 12.56 (s, IH), 7.98 (s, IH), 7.74 (s, IH), 7.65 -7.56 (m, 3H), 7.49 (t, J = 8.4 Hz, 2H), 7.28 (d, J = 8.5 Hz, 1 H), 7.21 (s, IH), 7.05 (s, IH), 3.91 (s, 3H), 3.09 (p, J = 7.3 Hz, IH), 1.11 (d, J = 7.0 Hz, 6H). LCMS MS m/z 444.4 [M+H]'.
79	Compound 677 from S8 A° Xj/oh H / n T £ Va F	0 cf3 MeoVjVjj Br	’HNMR (400 MHz, DMSOA)Ô 13.72 (s, IH), 12.62 (s, IH), 8.03 7.97 (m, 2H), 7.92 (s, IH), 7.85 (d, J = 8.2 Hz, IH), 7.67 - 7.60 (m, 2H), 7.55 - 7.47 (m, 2H), 7.34 (s, IH), 7.08 (s, IH), 3.18 (p, J = 7.2 Hz, IH), 1.14 (d, J = 7.1 Hz, 6H).LCMS m/z 482.4 [M+H]\

366

Compound	Method/Product	Aryl Halide	*H NMR; LCMS m/z [M+H]’
80	Compound 671,3 from S8 V-OH M H /N vXXX\ F	OMe Br^Z	‘HNMR (400 MHz, MethanolZ) δ 7.96 (s, IH), 7.54- 7.46 (m, 2H), 7.41 - 7.25 (m, 5H), 7.14 (s, IH), 6.99 (s, IH), 3.62 (s, 2H), 2.99 (dq, J = 13.9, 7.2 Hz, IH), 2.14 (s, 3H), 1.17 (d, J = 7.0 Hz, 3H), 1.00 (d, J = 7.1 Hz, 3H). LCMS m/z 442.4 [M+H]+.
81	Compound 675 from S8 VOH H / N JT L Vf 0 F	,OMe ''ZwF XX Br	’HNMR (400 MHz, DMSOZ,) δ 12.58 (s, IH), 8.27 (d, J = 1.8 Hz, IH), 7.97 (s, IH), 7.63 7.56 (m, 2H), 7.48 (t, J = 8.5 Hz, 2H), 7.27 (s, IH), 7.03 (d, J = 4.5 Hz, 2H), 6.94 (d, J = 9.9 Hz, IH), 3.16-3.13 (m, 1H),2.33 (s, 3H), 1.13 (d, J = 7.1 Hz, 6H). LCMS m/z 446.4 [M+H]+.
82	Compound 673,9from S8 HO V oÀz H / N-Z\Z / ùXXV 0 F	0^0 Me T^° Br 0^ OH	'HNMR (400 MHz, Chloroform-d) δ 7.98 (s, IH), 7.95 - 7.79 (m, 2H), 7.50 - 7.37 (m, 3H), 7.33 - 7.17 (m, 3H), 7.09 (s, IH), 4.20-4.03 (m, 2H), 3.76 - 3.59 (m, 2H), 3.17 -3.02 (m, IH), 1.09 (dd, J = 15.2, 6.9 Hz, 6H). LCMS m/z 474.4 [M+Lff. _

367

Compound	Met h od/Pro duct	Aryl Halide	*H NMR; LCMS m/z [M+H]+
83	Compound 676 from S8 OH FS MeO'A^ H / 0 F	Ος^ΟΜθ MeO. F. IJ Br'	’HNMR (400 MHz, DMSO-d6) δ 12,97 (s, IH), 12.53 (s, IH), 7.98 (s, IH), 7.71 (d, J = 7.6 Hz, IH), 7.64- 7.56 (m, 2H), 7.55 - 7.46 (m, 3H), 7.31 (t, J = 7.6 Hz, IH), 7.06 (d, J =11.2 Hz, 2H), 3.41 (s, 3H), 3.05 (p, J = 7.1 Hz, IH), 1.11 - 1.03 (m, 6H).LCMS m/z 444,4 [M+H]+.
84	Compound 673 from S8 O, y-OH W H F / n Ύ F/J F	/=\ O ”F U 0Z 0 / œ Tl	'HNMR (400 MHz, Méthanol δ 8.38 (d, J = 8.0 Hz, IH), 8.12 (d, J = 8.1 Hz, IH), 8.00 (s, 1 H), 7.61 -7.53 (m, 2H), 7.41 (t, J = 8.0 Hz, 2H), 7.19 (s, IH), 7.03 (s, IH), 6.69 (t, J = 53.9 Hz, IH), 3.03 (dq,J= 13.4, 6.6, 6.1 Hz, IH), 1.09 (dd, J = 44.3, 7.1 Hz, 6H).LCMS m/z 465.2 [M+H]0
85	Compound 67i2 from S8 Οχ y-OH y-N H / 'yj F	P ro—/ J \=/ o g (D	‘H NMR (400 MHz, DMSO<4)6 13.31 (s, IH), 12.68 (s, IH), 9.22 (s, IH), 8.39 (d, J = 8.3 Hz, IH), 8.01 (s, IH), 7.83 (d, J = 8.2 Hz, IH), 7.72 (s, IH), 7.63 (t, J = 6.0 Hz, 2H), 7.51 (t, J = 8.6 Hz, 3H), 7.06 (s, IH), 1.21 (d, J = 7.1 Hz, 6H). LCMS m/z 415.3 [M+H] .

368

Compound	Method/Product	Aryl Halide	‘H NMR; LCMS m/z [M+Hf
86	Compound 671,3 from S8 Os y-OH H / vio-/ F	OMe O<i χ) OMe	‘H NMR (400 MHz, Methanol-JQ δ 7.72 (s, IH), 7.49 (s, 2H), 7.377.30 (m, 4H), 7.21-7.03 (m, 3H), 3.76 (s, 3H), 3.37 (s, 2H), 3.10-3.02 (m, IH), 1.13 (d,J= 6.9 Hz, 3H), 1.06 (d, J =6.9 Hz, 3H). LCMS m/z 458.4 [M+H]+.
87	Compound 6713 from S8 H N 0 ITM —\X oh H / N-AA-A / nXjCa F	Ox^OMe χΐ HN^y^Br	‘H NMR (400 MHz, DMSOA) Ô 12.63 (s, IH), 12.44 (s, IH), 11.58 (s, IH), 8.11 (t, J = L2 Hz, IH), 7.98 (d, J= 1.0 Hz, 1 H), 7.73 - 7.63 (m, 3H), 7.55 (t, J = 2.8 Hz. IH), 7.50 (t, J = 8.7 Hz. 2H), 7.09 (d, J = 1.1 Hz, IH), 6.97 (t, J = L1 Hz, IH), 6.23 -6.17 (m, IH), 3.08 (p, J = 7.1 Hz, IH), 1.12 (d, J = 7.1 Hz, 3H), 0.98 (d, J = 7.1 Hz, 3H). LCMS m/z 453.4
88	Compound 6711 from S8 °yoH F NH s Yf H / νΛΓΠ x F	OxxOMe AA H sX* Br	‘H NMR (400 MHz, DMSO4) δ 12.64 (s, IH), 12.55 (br s, IH), 11.93 (s, IH), 8.00 (s, IH), 7.63 (dd, J = 8.8, 5.0 Hz, 2H), 7.54 - 7.46 (m, 3H), 7.09 (s, IH), 7.06 (d, J = 1.1 Hz, IH), 7.01 (d, J = 0.7 Hz, 1 H), 3.25 (sept, J = 7.1 Hz, IH), 1.20 (d, J = 7.2 Hz, 6H). LCMS m/z 473.3 [M+H]+.

369

Compound	Method/Produet	Aryl Halide	'H NMR; LCMS m/z [M+Hf
89	Compound 6789from S8 οχοΗ Γζ H / \X Xa P F	ll O )=\ O z^	XNMR (400 MHz, DMSO-î/6)Ô 13.59 (s, IH), 12.67 (s, 1H), 8.65 (s, IH), 8.07-7.96 (m, 2H), 7.67 - 7.5S (m, 2H), 7.52 (t, J = 8.6 Hz, 2H), 7.38 (s, IH), 7.09 (s, IH), 3.23-3.12 (m, IH), 1.14 (d, J = 7.1 Hz, 6H). LCMS m/z 433.3 [M+Hf.
90	Compound 671 from S8 J' o n=X// ΧΧ° H Γ xï L Vx F	OMe Bip ^1+ X 'A O X ΌΙ	‘H NMR (400 MHz, DMSO-J6) δ 14.34 (s, IH), 12.76 (s, IH), 8.92 (s, IH), 8.03 (s, IH), 7.78 (s, IH), 7.67-7.60 (m, 2H), 7.53 (t, J = 8.4 Hz. 2H),7.10(s, IH), 3.303.26 (m, IH), 1.21 (d, J = 7.1 Hz, 6H). LCMS m/z 450.3 [M+Hf.
91	Compound 6712 from S8 OH N l H / ΧζχΧΧ Q F	0^0 Me nJ X J Br'^	‘H NMR (400 MHz, DMSO-<Z6)0 13.16 (s, IH), 12.65 (s, IH), 8.11 (t, J = 7.7 Hz, IH), 8.057.96 (m, 2H), 7.90 (d, IH), 7.67-7.58 (m, 3H), 7.52 (t, J = 8.5 Hz, 2H), 7.08 (s, IH), 3.27-3.19 (m, IH), 1.22 (d, J = 7.1 Hz, 6H). LCMS m/z 415.4 [M+Hf.

370

Compound	Method/Product	Aryl Halide	’H NMR; LCMS m/z [M+H]+
92	Compound 678 from S8 0. n-oh —X d γ—N H Γ ό F	0^0 Me [îl Aj Br	‘H NMR (400 MHz, DMSO-dQ 5 I3.39(s, IH), 12.54 (s, IH), 9.02 (s, IH), 8.28 (s, IH), 8.00 (s, IH), 7.67 - 7.57 (m. 2H), 7.55 - 7.45 (m, 2H), 7.15 (s, 1 H), 6.92 (s, 11-1), 2.93 (p, J = 7.2 Hz, IH), 2.26 (s, 3H), 1,18 (d, J = 6.9 Hz, 3H), 0.87 (d, J = 7,0 Hz, 3 H).LCMS m/z 429.4 [M+H]\
93	Compound 678 from S8 y0H N. V V-N H Γ nXjO-/ F	LU HV* o “Z	'H NMR (400 MHz, Methanol-di) δ 9,32 (s, 2H), 8.71 (s, IH), 7.99 (s, IH), 7.59-7.51 (m, 2H), 7.42 (t, J = 8.1 Hz, 2H), 7.06 (s, IH), 4.22-4.10 (m, IH), 1.36 (d, J = 7.1 Hz, 6H). LCMS m/z 416.4 [M+HJL
94	Compound 67l2from S8 O f-Vn °h H Γ %ΧΧΥ~Λ F	ώ O Z A -W a^-	'HNMR (400 MHz, DMSOA) δ 13.30 (s, IH), 12.62 (s, IH), S.16 (dd, J = 8.6, 3.7 Hz, IH), 8.05 (d, J = 9.1 Hz, IH), 8.01 (s, IH), 7.64 (dd, J = 8.3, 5.0 Hz, 2H), 7.52 (t, J = 8.4 Hz, 2H), 7.27 (s, IH), 7.12 (s, IH), 3.04 (hept, J = 6.7, 6.2 Hz, IH), 1,14 (d, J = 7.0 Hz, 6H). LCMS m/z 433.3 [M+H]+.

37I

Compound	Method/Product	Aryl Halide	’H NMR; LCMS m/z [M+H]”
95	Compound 67l2from S8 OH / F O H / ç F	O LL S X ° A A # o zzy	‘HNMR (400 MHz, DMSO-if6) Ô 13.59 (s, IH), 12.67 (s, IH), 8.05 7.97 (m, 2H), 7.97 - 7.89 (m, IH), 7.66 -7.56 (m. 3H), 7.51 (t, J = 8.5 Hz, 2H), 7.08 (s, 1 H), 3.27 3.13 (m, IH), 1.20 (d, J = 7.0 Hz, 6H). LCMS m/z 433.5 [M+H]’.
96	Compound 678 from S8 O. yOH NO Me F	O^OMe γ OMe Br	’HNMR (400 MHz, Methanol-rf4) δ 8.84 (s, IH), 8.09 (s, IH), 7.96 (s, IH), 7.58 -7.50 (m, 2H), 7.39 (t, J = 8.3 Hz, 2H), 7.13 (d, J = 11.7 Hz, 2H), 3.90 (s, 3H), 3.06 (p, J = 7.2 Hz, IH), 1.10 (d, J = 7.1 Hz, 6H). LCMS m/z 445.4 [M+H]1.

Compounds 70, 71, 76, 80, 86, 90: Purification by reversed-phase HPLC. Method: C18 Waters Sunfîre column (30 xl50 mm, 5 micron). Gradient: 10-100% MeCN in H₂O afforded product in step I.

Compounds 71, 76: A second eq. of NaOH was added and the reaction was run overnight 5 în step 2. Purification by reverse phase column chromatography (Eluent: 10-100% acetonitrile in water with 0.2 % Formic Acid modifier) afforded the desired product in step 2.

Compound 72, 76, 77, 80, 81, 82, 84, 86, 88: Purification by reverse phase column chromatography (Eluent: 10-100% acetonitrile in water with 0.2% Formic Acid 10 modifier) afforded the desired product in step 2.

⁴' Compounds 70, 72: NMR showed atropisomers.

⁵‘ Compound 72: Purification by silica gel column chromatography of (Eluent: 0-40 % ethyl acetate in heptane) afforded the product în step 1.

⁶’ Compound 73, 83: Purification by silica gel column chromatography (Eluent: 0-80 % 15 DCM in heptane) afforded the product in step 1.

y

Compound 75, 79: Purification by silica gel column chromatography (Eluent: 0-100% CH₂Cl₂ in heptane) afforded the product in step 1.

372

Compound 75, 78, 92, 93, 96: Purification by reverse phase column chromatography (Eluent: acetonitrîle in water with 0.1 % formic acid modifier) afforded the desired product în step 2.

Compound 77, 82: Organics were passed through a silica gel plug, using dichloromethane and ethyl acetate as eluents instead of column chromatography for purification in step 1.

¹⁰* Purification by silica gel column chromatography (Eluent: 0-100% EtOAc:heptane) afforded the product in step 1.

Compound 88: Upon compietion of step 2 HCl IM and CHC1₃: IPA (3:1) was added, and the mixture was extracted with CHC1₃: IPA (3:1, 3 x). The organic phases were combined, dried with MgSO₄, filtered, and the volatiles were evaporated in vacuo to afford the product.

Compound 74, 85, 89, 91, 94, 95: Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: 10-100 % MeCN in H₂O afforded the product in step 2.

^l3· Compound 87: After addition of HCl in step 2 added water and extracted with ethyl acetate. Dried organic layer with sodium sulfate, filtered and removed solvent in vacuo.

Compound 97

2-fluoro-4-[5- (4-fhiorophenyl)-6-isopropyH-pyrrolo[2,3-f]indazol- 7-yl]benzoic acid

(97) ΑΛ z/ r T 0Me 1 hœbAJ ° / OH vi n ----- \ Pd(dppf)CI2 Na2CO3 y S9 F V-oh f'yF NaOH JJ Piperdine h / y J JL Vf 0 97 'F

ω S u. jyy T W11· \ / co o r\ °

373

Step 1: methyl 2-fluoro-4-[5-(4-fluorophenyl)-6-isopropyl-l-(p-tolylsulfonyl)pyrrolo[2,3f] indazol- 7-yl]benzoate 5-(4-fluorophenyl)-6-isopropyl-I-(p-tolylsulfonyl)pyrrolo[2,3-f]indazole (C84).

To a solution of 5-(4-fluorophenyl)-7-iodo-6-isopropyl-l-(p-tolylsulfonyl)pyrrolo[2,3i]indazole (200 mg, 0.34 mmol) S9, and Pd(dppf)Cl₂ (15 mg, 0.018 mmol) in 1,4-dioxane (5 mL) under nitrogen was added sodium carbonate (approximately 488.8 pL of 2 M, 0.98 mmol). N itrogen was run through the reaction mixture for 10 min. The reaction was heated at 100 °C for 60 min in a microwave reactor. Further boronic acid (50 mgs), Pd(dppf)Cl₂ ( 15 mg), and sodium carbonate (approximately 0.3 mL of 2 M solution) were added to the solution and heated to 110 ^UC for one h in a micro wave reactor. Water and EtOAc were added and the mixture was extracted with EtOAc (x 3). The organic layer was collected, dried with Na₂SO_4ï fîltered, and the solvent was removed in vacuo. Purification by silica gel column chromatography (Gradient: ΟΙ 00 % dichloromethane in heptane, followed by Gradient: 0-20 % EtOAc in dichloromethane) afforded the product (154 mg, 70 %). LCMS m/z 600.5 [M+H]⁺.

Step 2: 2-fluoro-4-[5-(4-fluorophenyl)-6-isopropyl-lH-pyrrolo[2,3-f]indazol-7-yl]benzoic acid (97)

To a solution of 2-fluoro-4-[5-(4~fluorophenyl)-6-isopropyl-l -(ptol y lsulfonyl)pyrrolo [2,3-f]indazol-7-yl] benzoate C84 (154 mg, 0.26 mmol) in THF (4 mL) and MeOH (2 mL) was added piperidine (51 pL, 0.52 mmol) and NaOH (1.3 mL of 1 M, 1.3 mmol). The solution was heated to 50 °C for 90 min. The solvent was removed in vacuo and 1M HCl (1.6 mL) was added. The solution was extracted with dichloromethane (x 3). The organic layer was collected, dried with Na₂SO₄, fîltered, and the solvent was removed in vacuo. Purification by silica gel column chromatography (Eluent: 0-6 % methanol in dichloromethane) afforded the product (52 mg, 43 %). *H NMR (300 MHz, DMSO-ri₆) δ 13.21 (s, IH), 12.61 (s, IH), 8.16 7.87 (m, 2H), 7.61 (ddt, J = 8.5, 5.6, 2.8 Hz, 2H), 7.56 - 7.37 (m, 4H), 7.35 (t, J = 1.1 Hz, IH), 7.06 (d, J = Ll Hz, IH), 3.18 (q, J = 7.2 Hz, IH), 1.14 (d, J = 7.2 Hz, 6H). LCMS m/z 432.3 [M+H]¹.

Compounds 98-99

Compounds 98-99 (see Table 8) were prepared in two steps from intermediate S9 using the appropriate boronic acid reagent, and using the coupling and deprotection method as described for compound 97. Modifications to method are noted in Table 8 and accompanying footnotes.

374

Table 8. Method ofpréparation, structure, physicochemical data for compounds 98-99

Compound	Method/Product	Boronic Acid	rH NMR; LCMS m/z [M+H] +
98	Compound 971 from S9 X-OH R/ H / n. X ΓΧ F	\ 1 0 o 0 0 r i/ x	’HNMR (300 MHz, DMSO-^jS 13.91 (s, 1 H), 12.62 (s, IH), 8.01 (d, J = 1.0 Hz, IH), 7.63-7-57 (m, 2H), 7.50 (dd, J = 9.9, 7.6 Hz, 2H), 7.37 (t, J= 1.1 Hz, IH), 7.31 (d, J = 9.2Hz, 2H), 7.06 (d, J = 1.1 Hz, IH), 3.19 (p, J = 6.9 Hz, IH), 1.14 (d, J = 7.2 Hz, 6H). LCMS m/z 450.3 [M+H]”.
99 1. -r .	Compound 972 from S9 X-OH N Xjz H / N / XX jX\ Q F	O^O Me XN 1 n Xoh	’H NMR (300 MHz, DMSO-rf6)Ô 12.66 (s, IH), 8.78 (dd, J = 2.2, 0.9 Hz, IH), 8.18 (dd, J = 8.0, 0.8 Hz, IH), 8.07 (dd, J = 8.0, 2.2 Hz, IH), 8.01 (d, J = 1.0 Hz, IH), 7.63 (ddt, J = 8.4, 5.6,2.8 Hz, 2H), 7.57 7.41 (m, 2H), 7.31 (t, J = 1.1 Hz, IH), 7.09 (d, J = 1.1 Hz, IH), 3.14 (p, J = 7.1 Hz, IH), 1.13 (d, J = 7.2 Hz, 6H). LCMS m/z 415.3 [M+H]’.

% graphy m step dichloromethane) afforded the product.

Purification by silica gel column chromatography (Solvent A: 20 % MeOH in CH2CI2 (containing 7 M NH₃ în MeOH). Solvent B: MeOH (containing 7 M NH₃). Gradient: 090 % solvent A: solvent B) afforded the product.

375

Compound 100

2-[4-[5-(4-fluorophenyl)-6-isopropyl-lH-pyrrolo]2,3-f]indazol- 7-yl]phenoxy] acetic acid (100)

Step 1: 2-[4-[5-(4-fluorophenyl)-6-isopropyl-l-(2-trimethylsilylethoxymethyl)pyrrolo[2,3 -

j]indazol-7-yl]phenoxy]acetic acid (C85)

To a solution of 2-[[5-(4-fluorophenyl)-7-iodo-6-isopropyI-pyrrolo[2,3-f]indazol-Iyl]methoxy]ethyl-trimethyl-silane S10 (100 mg, 0.18 mmol), [4-(2-ethoxy-2-oxoethoxy)phenyl]boronic acid (80 mg, 0.4 mmol), and Pd(PPh₃)₄ (10 mg, 0.009 mmol) in DMF (1.8 mL) was added Na₂CO₃ (450 pL of 2 M, 0.9 mmol). The reaction was heated at 125 °C for 10 60 min. The reaction was diluted in dichloromethane and water, and further extracted with dichloromethane (x 3). The organic phase was collected through a phase separator and the solvent was removed in vacuo. Purification by reverse phase column chromatography (Eluent: acetonitrile in water with 0.1 % Formic Acid modifier) afforded the desired product along with some of compound 100 (deprotected compound). The mixture was used in the next step without 15 séparation. LCMS m/z 574.3 [M+H] \

Step 2: 2-[4-[5-(4-fluor opheny l)-6-isopropyl-lH-pyrrolo [2,3-f] indazol-7-yl]phenoxy] acetic acid (100)

To a solution of 2-[4-[5-(4-fluorophenyl)-6-isopropyl-l-(2trimethylsilylethoxymethyl)pyrrolo[2,3-f]indazol-7-yl] phenoxy] acetic acid (C85 crude from step

376

l) in THF (1 mL) was added ethane-l,2-diamine (62 pL, 0,93 mmol). The reaction was stirred for 2 h at room température. Water and dichloromethane were added and the solution was extracted with dichloromethane (x 3), The organic phase was collected through a phase separator and the solvent was removed in vacuo. Purification by reverse phase column chromatography 5 (Eluent: 0 % - 40 % acetonitrile in water with 0.2 % formic acid modifier) afforded the product (23.5 mg, 28 %). ^!H NMR (400 MHz, Methanol-J₄) δ 7.94 (s, IH), 7.48 (m, 2H), 7.38 (m, 4H), 7.25 (s, IH), 7.08 (m, 3 H), 4.73 (d, J = 1.6 Hz, 2H), 3.13 (septet, J = 7.3 Hz, IH), 1.14 (d, J = 7.2, 6H). . LCMS m/z 444.2 [M+H]⁺.

Compound 101

3-fluoro-5-[5-(4-fluorophenyl)-6-isopropyl-lH-pyrrolo[2,3-J]indazol- 7-yljbenzoic acid (101)

377

Step 1. 5-(4-fluorophenyl)-7-iodo-6-isopropyl-N,N-dimethyl-pyrrolo[2,3-j]indazole-lsulfonamide (C86)

5-(4-fluorophenyl)-7-iodo-6-isopropyl-lH-pyrrolo[2,3-f]indazole C24 (306 mg, 0.7 mmol) was dissolved in THF (3.6 mL) and cooled in an ice bath. KOtBu (103 mg, 0.92 mmol) was added and the mixture stirred for 5 min. Ν,Ν-dimethylsulfamoyl chloride (90 pL, 0.84 mmol) was added and the reaction allowed to stir for 1 h. Aqueous NH4Cl_(sat.) was added, then water and dichloromethane were added. The phases were separated on a phase separator. Purification by silica gel chromatography (Eluent: Ethyl acetate in CH2CI2) afforded the product (147 mg, 40 %). ‘H NMR (400 MHz, DMSO) δ 3.00 (p, J = 7.0 Hz, 4FI), 2.89 (d, J = 1.1 Hz, 30H), 1.33 (d, J = 7.1 Hz, 30H), 2.80 - 2.75 (m, 0H), 8.83 (s, 5H), 7.6S - 7.37 (m, 26H), 7.02 (s, 5H). LC MS m/z 527.2 [M+l]+.

Step 2. methyl 3-[l-(dimethylsulfamoyl)-5-(4-fluorophenyl)-6-isopropyl-pyrrolo[2,3-f]indazol-7yl]-5-fhioro-benzoate (C87)

A solution ot 5-(4-fluorophenyl)-7-iodo-6-isopropyl-N,N-dimethyl-pyrrolo[2,3f]indazole-l-sulfonamide C86 (54 mg, 0.10 mmol), (3-fluoro-5-methoxycarbonylphenyl)boronic acid (30 mg, 0.1515 mmol) and Pd(dppf)Cl₂ (8 mg, 0.01 mmol) in DMF (350 pL) was microwaved at 90 °C for 30 min. The reaction was diluted in dichloromethane and water. The organic phase was collected through a phase separator and the solvent was removed in vacuo. Purification by silica gel column chromatography (Eluent: 0-100% EtOAc in dichloromethane) afforded the product (26 mg, 46 %). LCMS m/z 553.4 [M+H]⁺.

Step 3. methyl 3-fluoro-5-[5-(4-fluorophenyl)-6-isopropyl-lH-pyrrolo[2,3-f]indazol-7yl] benzoate (C88)

To a solution of methyl 3-[l-(dimethylsulfamoyl)-5-(4-fluorophenyl)-6-isopropylpyrrolo[2,3-f]indazol-7-yl]-5-fluoro-benzoate C87 (26 mg, 0.05 mmol) in CH₂C1₂ (300 pL), was added anisole (15 pL, 0.14 mmol) and TFA (100 pL). The solution was stirred at room température for 48 h. The solvents were removed in vacuo and the crude product used directly in the next step without further purification. LCMS m/z 446.3 [M+H]⁺.

Step 4. 3-fluoro-5-[5-(4-fiuorophenyl)-6-isopropyl-lH-pyrrolo[2,3-fJindazol- 7-yl]benzoic acid (101)

To a solution of methyl 3-fluoro-5-[5-(4-fluorophenyl)-6-isopropyI-lH-pyiToIo[2,3f]indazol-7-yl]benzoate C88 (25 mg, 0.04 mmol) in MeOH (150 pL) and THF (300 pL) was added sodium hydroxide (175 pL of 2 M, 0.4 mmol). The reaction was stirred at 55 C for 2 h. Water (1 mL) was added and the organic solvents were removed in vacuo. The pH of the solution was adjusted to pH 3 and the water was removed in vacuo. Purification by reverse phase column chromatography (Eluent: acetonitrile in water with 0.1 % Formic Acid modifier) 378 followed by silica gel column chromatography (Eluent: dichloromethane in methanol) afforded the product (8.7 mg, 52 %). ^]H NMR (400 MHz, DMSO-î/₆) δ 12.59 (s, IH), 8.00 (s, IH), 7.91 (s, IH), 7.79 - 7.39 (m, 7H), 7.30 (s, IH), 7.07 (s, IH), 3.24 - 2.96 (m, IH), 1.13 (d, J = 7.1 Hz, 6H). LCMS m/z 432.32 [M+H]⁺.

Compound 102

4-(6-isopropyl-5-phenyl-lH-pyrrolo[2,3-f]indazol-7-yl)benzoic acid (102)

NaOtBu (36 mg, 0.37 mmol), BrettPhos Pd G1 (22 mg, 0.03 mmol), 3-(4-fluorophenyl)IH-pyrazole (18 mg, 0.1 mmol) and 4-[5-(4-fluorophenyl)-6-isopropyl-lH-pyrrolo[2,3f]indazol-7-yl]benzoic acid 51 (50 mg, 0.12 mmol) were added to a vial under a nitrogen atmosphère. Propan-2-ol (1.5 mL) was added, and the mixture further purged with nitrogen, then heated in a microwave for 180 min at 150 °C. The mixture was concentrated to dryness in vacuo. IM HCl was added and the mixture was extracted with EtOAc. The organic layer was dried over sodium sulfate, and concentrated in vacuo. Purification b y reversed phase chromatography (Column: Cl8. Gradient: 20-100 % MeCN in water with a 0.2 % fonnic acid), then HPLC (Gradient: 20-100 % MeCN in water with a 0.2 % fonnic acid) to afford the product (23.9 mg, 54 %). *H NMR (300 MHz, DMSO-rf₆) δ 12.96 (s, IH), 12.57 (s, IH), 8.13 - 8.06 (m, 2H), 7.99 (d, J = 1.0 Hz, IH), 7.71 - 7.58 (m, 5H), 7.5S - 7.52 (m, 2H), 7.30 (t, J = 1.1 Hz, IH), 7.04 (d, J = l.l Hz, IH), 3.19 (p, J = 7.0 Hz, 1 H), 1.13 (d, J = 7.2 Hz, 6H). LCMS m/z 396.3 [M+l]+.

379

Compound 103 & 104

4-/5-(4-fluorophenyl)-lH-pyrrolo/2,3-f]indazoI-7-yl]benzoic acid (103) and 4-/5-(4fluorophenyl)-6-trimethylsilyl-lH-pyrrolo[2,3-fjindazol- 7-yl]benzoic acid (104)

Pd(OAc)_z

DTBPF KHC0₃

Step l. Synthesis of 6-bromo-N-(4-fluorophenyl)-1H-indazol-5-amine (C90)

A solution of 1-fluoro-4-iodo-benzene (1.6 mL, 13.9 mmol), 6-bromo-lH-indazol-5amine C89 (2000 mg, 9.4 mmol), NaOtBu (3.9 g, 40 mmol), and tBuXPhos Pd G4 (432 mg, 0.48 mmol) tBuOH (50 mL) degassed and purged with nitrogen. The mixture was allowed to stir at room temperature for 5 h. The mixture was diluted with ethyl acetate, washed with 50 % saturated sodium bicarbonate, and then by brine. The organic layer was dried over with sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (Gradient: 0-100 % EtOAc in heptane) afforded the product (1.8 g, 62 %). ’H NMR (400 MHz, DMSO) δ 13.06 (s, 380

IH), 7.99 (s, IH), 7.89 (s, IH), 7.59 (s, IH), 7.48 (d, J = 1.7 Hz, IH), 7.09 - 6.88 (m, 2H), 6.80 (dd, J = 8.1, 4.7 Hz, 2H). LCMS m/z 305.9 [M+H]⁺.

Step 2. Synthesis c/T-[6-bromo-5-(4-fluoroaniIino)indazol-I-yl]-2,2-dimethyI-propan-l-one (C91)

To a solution of 6-bromo-N-(4-fluorophenyl)-l H-indazol-5-amine C90 (754 mg, 2.4 mmol) in THF (15 mL) at 1 °C (ice-water bath) was added KOtBu (2.6 mL of 1 M, 2.6 mmol) After ~10 min, 2,2-dimethylpropanoyl chloride (340 pL, 2.7 mmol) was added and the mixture stirred for 30 min in cooling bath. An additional 25 pl of 2,2-dimethylpropanoyl chloride was added and the mixture stirred for another -30 min in the ice bath. The reaction was quenched with water (3 mL), stirred for 5 min and the concentrated to dryness in vacuo. The residue was diluted with CH₂C1₂, (20 mL) and washed with water (10 mL). The organic phase was passed through a phase separator and concentrated to dryness in vacuo to afford the product (971 mg, 100 %). 'H NMR (300 MHz, DMSO-ri₆) δ 8.61 - 8.56 (m, IH), 8.36 (d, J = 0.9 Hz, IH), 7.62 (s, IH), 7.57 (s, IH), 7.16 - 7.04 (m, 4H), 1.49 (s, 9H). LCMS m/z 3962 [M+H]⁺.

Step 3. Synthesis of methyl 4-[ 1 -(2,2-climethylpropanoyl)-5-(4-Jluorophenyl)pyrrolo[2, ΙΑ indazol-7-yl] benzoate (C92) l-[6-bromo-5-(4-fluoroanilino)indazol-l-yl]-2,2-dimethyl-propan-l-one C91 (511.3 mg, 1.3 mmol), methyl 4-(2-trimethylsilylethynyl)benzoate (362.2 mg, 1.6 mmol), Pd(OAc)₂ (17.2 θ·θ8 mmol), DTBPF (73 mg, 0.15 mmol), and KHCO3 (650 mg, 6.5 mmol) were added to a vial and the mixture degassed and purged with nitrogen. NMP (2.5 mL) was added and the mixture was flushed with nitrogen. The mixture was heated to 110 °C for 1 h. The reaction mixture was diluted with CH₂Cl_2h and washed with water. The organic phase was passed through a phase separator, and concentrated in vacuo. Purification b y silica gel chromatography (0-100 % ethyl acetate in heptane) afforded the product C92 (240 mg, 38 %). *H NMR (300 MHz, DMSO-A δ 8.98 (s, IH), 8.57 - 8.53 (m, IH), 8.43 (s, IH), 8.13 (d, J = 8.3 Hz, 2H), 8.06 (d, J = 1.0 Hz, IH), 7.97 (d, J = 8.4 Hz, 2H), 7.83 (dd, J = 8.9, 4.8 Hz, 2H), 7.52 (t, J = 8.7 Hz, 2H), 3.90 (s, 3H), 1.54 (s, 9H). LCMS m/z 470,4 [M+l]⁺. X-ray crystallography confirmed the regiochemistry of the product.

Step 3. Synthesis of methyl 4-[l-(2,2-dimethylpropanoyl)-5-(4-fluorophenyl)-6-trimethvlsilylpyrrolo]2,3-f]indazol- 7-yl]benzoate (C93)

I - [6-bromo-5-(4-fluoroanilino)indazol-l-yl]-2,2-dimethyl-propan-1-one C91 (460 mg, I 17 mmol), methyl 4-(2-trimethylsilylethynyl)benzoate (325 mg, 1.40 mmol), Pd(OAc)₂ (16 mg, 0,07 mmol), DTBPF (66 mg, 0,14 mmol), and KHCO3 (585 mg, 5.8 mmol) were added to a vial and the mixture degassed and purged with nitrogen. NMP (2.5 mL) was added the mixture purged with additional nitrogen. The mixture was heated to 110 °C for 1 h. The reaction mixture 381 was diluted with CH2CI2, and washed with water. The organic phase was passed through a phase separator, and concentrated in vacuo. The product C93 was obtained as a mixture with des-TMS product C92 and other regioisomers. Purification by silica gel chromatography (Gradient: ΟΙ 00 % ethyl acetate in heptane) afforded C93. Structure confirmed by x-ray crystallography.

Methyl 4-[I-(2,2-dimethylpropanoyl)-5-(4-fluorophenyl)-6-trimethylsilyl-pyrrolo[2,3-f]indazoI7-yl]benzoate C93 (195 mg). ^fH NMR (300 MHz, DMSO-tf₆) δ 8.46 (d, J = 0.8 Hz, IH), 8.35 (t, J = 0.9 Hz, IH), 8.18 - 8.11 (m, 2H), 7.72 - 7.62 (m, 4H), 7.57 - 7.46 (m, 3H), 3.92 (s, 3H), 1.47 (s, 9H), -0.14 (s, 9H). LCMS m/z 542.3 [M+l]⁺.

Step 4. Synthesis of 4-[5-(4-fluorophenyl)-lH-pyrrolo[2,3-f]indazol-7-yl]benzoic acid (103)

To a solution of methyl 4-[ 1-(2,2-dimethylpropanoyl )-5-(4-fl uorophenyl)pyrrolo [2,3f]indazol-7-yI]benzoate C92 (9 mg, 0.02 mmol) in methanol (500 pL) and THF (500 pL) was added aqueous NaOH (200 pL of 1 M, 0.2 mmol) and stirred at 55 °C for 1 h. The mixture was concentrated to dryness in vacuo. EtOAc was added and the mixture was washed with 1M HCl. The organic layer was dried over MgSO₄, filtered and concentrated in vacuo. Purification by reversed-phase chromatography (Cl 8 column. Gradient: 10-100 % MeCN in water with a formic acid modifier) afforded the product (3.4 mg, 48 %). ‘H NMR (300 MHz, Methanol-^) δ 8.17 8.09 (m, 3H), 8.08 - 8.04 (m, IH), 7.97 (s, IH), 7.92 - 7.86 (m, 3H), 7.74 - 7.66 (m, 2H), 7.41 7.3 1 (m, 2H). LCMS m/z 372.2 [M+H]!

Step 5. Synthesis of 4-[5-(4fluorophenyl)-6-trimethylsilyl-lH-pyrrolo[2,3-f]indazol-7-yl]benzoic acid (104)

Compound 104 was prepared from C93 using the method described for préparation of 103 from C92. Purification by reversed phase chromatography (Cl8 column. Gradient: 50-80 % MeCN in water with an ammonium formate modifier), afforded the product (12.5 mg, 29 %). ^!H NMR (300 MHz, DMSO-4) δ 13.4-12.88 (bs, IH), 12.65 (s, IH), 8.15 - 8.02 (m, 3H), 7.70 7.56 (m, 4H), 7.49 (t, J = 8.7 Hz, 2H), 7.38 (t, J = 1.1 Hz, IH), 7.36 - 7.32 (m, IH), -0.14 (s, 9H). LCMS m/z 444.4 [M+H]⁺.

382

Compound 105

4-[5-(4-fluorophenyl)-6-(trifluoromethyl)-lH-pyrrolo[2,3-f]indazol-7-yl]benzoic acid (105)

Step 1. methyl 4-[l-(2,2-dimethylpropanoyl)'5-(4-fluorophenyl)-6-(trifluoromethyl)pyrrolo[2,35 fl indazol-7-yl] benzoate (C94)

A solution of methyl 4-[l-(2,2-dimethylpropanoyl)-5-(4-fluorophenyl)pyrroio[2,3f]indazol-7-yl]benzoate C92 (202 mg, 0.4 mmol) and 2,8-dîfluoro-5-(trifluoromethyl)-4a,9bdihydrodibenzothiophen-5-ium trifluoromethanesulfonate (365 mg, 0.83 mmol) in DMF (2 mL) and NMM (104 pL, 0.95 mmol) were heated at 50 °C ovemight. 1 N HCl (3 mL) was added and 10 the aqueous was extracted with CH_ZCL (8 mL x 3). The combined organic layers were dried and concentrated in vacuo. Purification by silica gel chromatography (Gradient: 0-100 % EtOAc in hexanes) to afford the product (40 mg, 16 %). ^lH NMR (300 MHz, Chloroform-d) δ 8.67 - 8.62 (m, IH), 8.23 - 8.16 (m, 2H), 8.13 (d, J = 0.8 Hz, IH), 7.64 (d, J = 8.2 Hz, 2H), 7.51 (dd, J = 8.8, 4.7 Hz, 2H), 7.35 - 7.30 (m, 3H), 3.99 (s, 3H), 1.56 (s, 9H). LCMS m/z 538.4 [M+H]⁺.

Step 2. 4-[5-(4-fluorophenyl)-6-(trifluoromethyl)-lH-pyrrolo[2,3-flindazol-7-yl]benzoic acid (105)

NaOH (500 pL of 1 M, 0.5 mmol) was added to a solution of methyl 4-[l-(2,2dim ethyl propanoyl)-5-(4-fluoro phenyl )-6-(tri fl uoromethyl)pyrrolo [2,3-f] indazol-7-yl]benzoate C94 (30 mg, 0.05 mmol) in methanol (1.5 mL) and THF (1.5 mL). The mixture was allowed to 20 stir for l h at 55 °C. The mixture was concentrated in vacuo. EtOAc was added and the mixture

383 washed with IM HCl. The organic layer was dried over MgSO₄, filtered and concentrated in vacuo. Purification by reverse phase chromatography ( i 0-100 % MeCN in water with a formic acid modifier) afforded the product (4.4 mg, 20 %). ^lH NMR (300 MHz, DMSO-î/₆) δ 12.8S (s, 1 H), 8.16 - 8.07 (m, 3H), 7.74 - 7.63 (m, 4H), 7.57 - 7.46 (m, 3H), 7.38 (d, J = L2 Hz, IH). LCMS m/z 440.4 [M+H]”.

Compound 106

4-[5-(4-fluorophenyl)-6-(l-hydroxy-l-methyl-ethyl)-lH-pyrrolo[2,3-f]indazol-7-yl]benzoic acid (106)

Step 1 .Synthesis of 6-chloro-N-(4-fluorophenyl)~lH-indazol-5-amine (C96) tBuOH (49 mL) (containing 10 % m-xylene) was added to a mixture of 5-bromo-6chloro-lH-indazole C95 (2.05 g, 8.9 mmol), 4-fluoroaniline (940 pL, 9.8 mmol), NaOtBu (2.6 g, 26.6 mmol), and tBuXPhos Pd G4 (410 mg, 0.46 mmol). The mixture was degassed and purged with nitrogen, and the mixture was allowed to stir at room température for 4 h. The mixture was concentrated in vacuo, then diluted with CH2CI2 The mixture was washed with water and then brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (Gradient: 0-100 % ethyl acetate in heptane) afforded the product (1.8 g, 79 %). ’H NMR (300 MHz, DMSO-g?₆) δ 13.04 (s, IH), 7.98 (t, J = 1.2 Hz, IH), 7.71 (d, J = 0.8 Hz, IH), 7.58 (s, IH), 7.53 (s, IH), 7.08 - 6.95 (m, 2H), 6.91 - 6.80 (m, 2H). LCMS m/z 262.1 [M+Hf.

384

Step 2. Synthesis of l-[6-chloro-5-(4-fluoroanilino)indazol-l-yl]-2,2-dimethyl-propan-l-one (C97)

To a suspension of 6-chloro-N-(4-fluorophenyl)-lH-indazol-5-amine C96 (1.84 g, 6.97 mmol) in THF (36 mL) at 1 °C (ice-water bath) was added KOtBu (7.36 mL of 1 M, 7.4 mmol). After -10 min, 2,2-dimethylpropanoyl chloride (965 pL, 7.8 mmol) was added and the mixture was stirred for 30 min. The reaction was quenched with water (10 mL), stirred for 5 min then concentrated in vacuo. The mixture was partitioned between CH₂C1₂ (100 mL) and water (50 mL). The organic layer was passed through a phase separator, and concentrated to dryness in vacuo. Purification by silica gel chromatography (Gradient: 0-100 % ethyl acetate in heptane) afforded the product (2.1 g, 86 %). ’H NMR (300 MHz, DMSO-î/₆) δ 8.41 - 8.37 (m, IH), 8.35 (d, J = 0.9 Hz, IH), 7.76 (s, IH), 7.57 (s, IH), 7.15 - 7.13 (m, 2H), 7.13-7.11 (m, 2H), 1.49 (s, 9H). LCMS m/z 331.7 [M+H]⁺.

Step 3. Synthesis of4-[l-(2,2-dimethylpropanoyl)-5-(4-fluorophenyl)-6-(l-hydroxy-l-methylethyl)pyrrolo[2,3-f]indazol-7-yl]benzoic acid (C98)

A mixture of 4-(3-hydroxy-3-methyl-but-l-ynyl)benzoic acid (69 mg, 0.34 mmol), l-[6chloro-5-(4-fluoroanilino)indazol-l-yl]-2,2-dimethyl-propan-l-one C97 (98 mg, 0.28 mmol), Pd(OAc)₂ (5 mg, 0.02 mmol), DTBPF (16 mg, 0.03 mmol), and K₂CO₃ (198 mg, 1.43 mmol) were added to a vial and the vessel evacuated and flushed with nitrogen (x 3). NMP (1 mL) was added and the mixture flushed with additional nitrogen (x 3). The mixture was heated to 110 °C for 1 h. EtOAc was added and the mixture washed with 1 M HCl. The organic layer was dried over Na₂SO₄, filtered and concentrated. Silica gel chromatography (Gradient: 0-10 % methanol in CH₂C1₂) afforded the product (72 mg, 50 %). 'H NMR (300 MHz, DMSOA₆) δ 13.00 (s, IH), 8.39 (d, J = 0.8 Hz, IH), 8.11 - 8.05 (m, 2H), 8.02 - 7.99 (m, IH), 7.61 - 7.53 (m, 4H), 7.43 (t, J = 8.7 Hz, 2H), 7.08 (d, J = 1.0 Hz, IH), 5.01 (s, IH), 1.44 (s, 9H), 1.33 (s, 6H). LCMS m/z 514.3 [M+H]⁺.

Step 4. 4-[5-(4-fluorophenyl)-6-(l-hydroxy-l-methyl-ethyl)-lH-pyrrolo[2,3-fJindazol-7yl]benzoic acid (106)

Aqueous NaOH (1 mL of 1 M, 1.0 mmol) was added to a solution of 4-[ 1-(2,2dimethylpropanoyl)-5-(4-fluorophenyl)-6-(l -hydroxy-1-methyl-ethyl)pyrrolo [2,3-t]indazoI-7yl]benzoic acid C98 (71 mg, 0.14 mmol) in methanol (2 mL) and THF (2 mL) and stirred over 1 h at 55 °C. The mixture was concentrated to dryness. EtOAc was added and the mixture washed with IM HCL The organic layer was dried over MgSO₄, filtered and concentrated in vacuo. Purification by silica gel chromatography (Gradient: 0-10 % methanol in CH₂C1₂) afforded the product (25.2 mg, 41 %). ’H NMR (300 MHz, DMSOA₆) δ 12.98 (s, 1 H), 12.51 (s, IH), 8.09 385

8.02 (m, 2H), 7.97 (d, J = l.0 Hz, IH), 7.61 - 7.50 (m, 4H), 7.40 (t, J = 8.8 Hz, 2H), 6.99 (t, J =

1.1 Hz, 1 H), 6.89 (d, J = 1.1 Hz, 1 H), 4.92 (s, 1 H), i .32 (s, 6H). LCMS m/z 430.2 [M+Hf.

Compound 107

4-[5-(4-fluorophenyl)-6f3-methyloxetan-3-yl)-lH-pyrrolo[2,3-f]indazol-7-yl]benzoic acid (107)

Step 1. Synthesis of 5-bromo-6-[2-(3-methyÎoxetan-3-yl)ethynyl]-lH-indazole (C99)

To a solution of 5-bromo-6-iodo-lH-indazole Cl (2 g, 6.2 mmol) in DMF (12.5 mL) under nitrogen was added 3-ethynyl-3-methyl-oxetane (626 pL, 6.2 mmol), diethylamîne (1.91

386 mL, 18.5 mmol), PdCLtPPfp)? (220 mg, 0.31 mmol) and Cul (88 mg, 0.45 mmol). The reaction mixture was heated to 90 °C for 1 h. The mixture was then concentrated and water and CH₂CL were added. The organic layer was concentrated in vacuo. Purification by silica gel chromatography (Eluent: Ethyl acetate in heptanes) afforded the product (1.04 g, 58 %). ‘H NMR (400 MHz, DMSO-rf₆) δ 13.37 (s, IH), 8.15 (t, J = 0.7 Hz, IH), 8.08 (t, J = 1.3 Hz, IH), 7.76 (t, J = 0.8 Hz, IH), 4.81 (d, J = 5.5 Hz, 2H), 4.48 (d, J = 5.5 Hz, 2H), 1.68 (s, 3H). LCMS m/z 291.1 [M+H]⁴.

Step 2. Synthesis of N-(4-βιιorophenyl)-6-[2-(3-methyloxetan-3-yl)ethynyl]-ll·l-indazol-5-amine (C100)

A solution of 5-bromo-6-[2-(3-methyloxetan-3-yl)ethynyI]-lH-indazole C99 (1.04 g, 3.6 mmol), 4-fluoroaniline (482 pL, 5.10 mmol), NaOtBu (608 mg, 6.33 mmol) in t-butanol (16.8 mL) was purged with N₂ for 10 min at 40 °C. tBuXPhos Pd G3 (56.7 mg, 0.07 mmol) was added and the mixture was purged with N₂ for an additional 10 min. The reaction was heated to 70 °C for 1 h. Additional 4-fluoroaniline (482 pL, 5.1 mmol), NaOtBu (608 mg, 6.3 mmol) and tBuXPhos Pd G3 (56.7 mg, 0.07 mmol) were added and the mixture stirred ovemight. Purification by silica gel chromatography (Gradient: 0-100 % EtOAc in heptane) afforded the product (568 mg, 48 %). ’H NMR (400 MHz, Methanol-^) δ 7.91 - 7.88 (m, 1 H), 7.60 (s, IH), 7.46 - 7.41 (m, IH), 6.96 (d, J = 6.6 Hz, 4H), 4.76 (d, J = 5.4 Hz, 2H), 4.42 (d, J = 5.6 Hz, 2H), 1.62(s,3H). LCMS m/z 322.3 [M+H]⁴.

Step 3. 5-(4-fluorophenyl)-6f3-methyloxetan-3-yl)-lH-pyrrolo[2,3-f]indazole (C101)

A solution of N-(4-fluorophenyl)-6-[2-(3-methyloxetan-3-yl)ethynyl]-lH-indazol-5amîne (518 mg, 1.5 mmol) in DMSO (2 mL) was heated at 150 °C for 2 h. Water was added and product precipitated out. Filtration of the solid precipitate afforded the product. 5-(4fluorophenyl)-6-(3-methyloxetan-3-yl)-l H-pyrroIo[2,3-f]indazole (466 mg, 90%). ^!H NMR (400 MHz, Methanol-ity) δ 7.96 (d, J = 1.0 Hz, IH), 7.59 (t, J = 1.0 Hz, IH), 7.44 - 7.3S (m, 2H), 7.37 - 7.29 (m, 2H), 7.11 - 7.08 (m, IH), 6.46 (s, IH), 5.12 (d, J = 5.5 Hz, 2H), 4.23 (d, J = 5.8 Hz, 2H), 1.64 (s, 3H). LCMS m/z 322.3 [M+H]⁴.

Step 4. Synthesis of l-[5-(4-fluorophenyl)-6-(3-methyloxetan-3-yl)pyrrolo[2,3-f]indazol-1-yl]2,2-dimethyl-propan-1 -one (Cl 02)

A solution of 5-(4-fluorophenyl)-6-(3-methyloxetan-3-yl)-lH-pyrrolo[2,3-f]indazole Cl01 (466 mg, 1.5 mmol) in THF (10.4 mL) was cooled to 0 °C. KOtBu (360 mg, 3.21 mmol) was added, and the mixture allowed to stir for 5 min. 2,2-dimethylpropanoyl chloride (692 pL, 5.6 mmol) dropwise, was added and the mixture allowed to stir at 0 °C for 1 h. Purification by silica gel chromatography (Gradient; 0 - 100 % EtOAc in dichloromethane) afforded the product (580 mg, 99 %). 'H NMR (400 MHz, Methanol-rf₄) δ 8.57 (s, 1 H), 8.14 (s, IH), 7.45 - 7.39 (m, 387

2H), 7.38 - 7.31 (m, 2H), 7.16 (s, IH), 6.58 (s, IH), 5.12 (d, J = 5.6 Hz, 2H), 4.24 (d, J = 5.7 Hz, 2H), 1.65 (s, 3H), 1.56 (s, 9H). LCMS m/z 406.4 [M+H]⁺.

Step 5. Synthesis of l-[5-(4-fluorophenyl)-7-iodo-6-(3-methyloxetan-3-yl)pyrroIo[2,3-f]indazoll-yl]-2,2-dimethyl-propan-l-one (Cl03) l-iodopyrroiidine-2,5-dione (414 mg, I.75 mmol) was added portionwise to a solution of l-[5-(4-fluorophenyl)-6-(3-methyloxetan-3-yl)pyrrolo[2,3-f]indazol-l-yl]-2,2-dimethyl-propanI-one C102 (580 mg, 1.43 mmol) in CH2CI2 (5.9 mL) at 0 °C and the reaction allowed to stir at room température for l h. The reaction mixture was washed with IM Na₂SO₃ and the organic phase collected through a phase separator to afford the product (513 mg, 68%). ’H NMR (400 MHz, DMSO-îX) δ 8.44 (d, J = 0.8 Hz, IH), 8.34 (t, J = 0.9 Hz, IH), 7.68 - 7.62 (m, 2H), 7.51 - 7.44 (m, 2H), 7.31 (d, J = 0.9 Hz, IH), 4.86 (d, J = 5.7 Hz, 2H), 3.97 (d, J = 5.8 Hz, 2H), 1.93 (s, 3H), 1.52 (s, 9H). LCMS m/z 532.4 [M+H]\

Step 6. Synthesis of ethyl 4-[l-(2,2-dimethylpropanoyl)-5-(4fluorophenyl)-6-(3-methyloxetan-3yl)pyrrolo[2,3-j]indazol-7-yl] benzoate (C104)

A mixture of l-[5-(4-fluorophenyl)-7-iodo-6-(3-methyloxetan-3-yl)pyrrolo[2,3f]indazol-l-yl]-2,2-dimethyl-propan-l-one Cl 03 (100 mg, 0.18 mmol), (4ethoxycarbonylphenyl)boronic acid (72 mg, 0.37 mmol) and Pd(dppf)Cl₂ (7.1 mg, 0.009 mmol) was placed în a vial. 1,4-dioxane (604 pL) and Na₂CO₂ (287 pL of 2 M, 0.6 mmol) were added and the reaction stirred at 95 °C for 1 h. Water and CH₂C1₂ were added and the phases were separated on a phase separator. Purification by silica gel chromatography (0-100 % EtOAc/dichloromethane) afforded the product. (44.6 mg, 45 %). LCMS m/z 554.5 [M+H]^-. Step 7. Synthesis of 4f5-(4-fluorophenyl)-6-(3~methyloxetan-3-yl)-lH-pyrrolo[2,3-f]indazol-7yl]benzoic acid (107)

NaOH (332 pL of 1 M, 0.33 mmol) was added to a solution of ethyl 4-[l-(2,2dimethylpropanoyl)-5-(4-fluorophenyl)-6-(3-methyfoxetan-3-yl)pyrrofo[2,3-f]indazol-7yl]benzoate C104 (45 mg, 0.073 mmol) in THF (918 pL) and MeOH (379 pL). The mixture was heated at 50 °C for 1 h. Concentration in vacuo, followed by reverse phase chromatography (Eluent: MeCN in water containing 0.1 % formic acid) afforded (21.1 mg, 63 %). ‘l-I NMR(400MHz, DMSO-X) δ 13.00 (s, IH), 12.66 (s, IH), 8.08 (d, J = 7.6 Hz, 2H), 8.01 (s, IH), 7.72 - 7.65 (m, 2H), 7.60 (d, J = 7.8 Hz, 2H), 7.51 - 7.44 (m, 3H), 7.04 (s, IH), 4.52 (d, J = 5.4 Hz, 2H), 3.65 (d, J = 5.2 Hz, 2H), 2.00 (s, 3H). LCMS m/z 442.4 [M+H]⁺.

388

Compound 108 4-[5-(4-fluorophenyl)-6-(4-methyltetrahydropyran-4-yl)-lH-pyrrolo[2,3-J]indazol-7-yl]benzoic acid (108)

Compound 108 was prepared from Cl and 4-ethynyl-4-methyI-tetrahydropyran in seven steps, in an analogous manner to the method described for the préparation of compound 107. Purification by reverse phase chromatography (Gradient: 0-100 % MeCN in water, containing 10 mM ammonium formate) afforded the product (2.1 mg, 20%). ^!H NMR (400 MHz, Methanol-^) δ 8.12 (d, J = 7.5 Hz, 2H), 7.94 (s, IH), 7.57 - 7.50 (m, 4H), 7.37 (t, J = 8.3 Hz,

389

2H), 7.04 (s, IH), 6.95 (s, IH), 3.57 - 3.39 (m, 4H), 1.92 (d, J = 14.8 Hz, 2H), 1.60 - 1.55 (m, 3H), 1.34- 1.24 (m, 2H). LCMS m/z 470.2 [M+Hf.

Compound 109

4-[5-(4-fluorophenyl)-6-(8-oxabicyclo[3.2. l]octan-3-yl)-lH-pyrrolo[2,3-j] indazol- 7-yl] benzoic acid (109)

Compound 109 was prepared from Cl and 3-ethynyl-8-oxabicyclo[3.2.1]octane in seven steps using the method described for the préparation of compound 107 and 108. Purification by reverse phase chromatography (Cl8 column. Gradient: 10-100 % acetonitrile in water with 0.2% fonnic acid) afforded the product was obtained as a w^rhite solid (11.9 mg). *H NMR (400 MHz, Methanol-A) δ 8.18 (d, J = 7.8 Hz, 2H), 7.98 (s, IH), 7.62 (d, J = 7.8 Hz, 2H), 7.53 (dd, J = 8.3, 4.6 Hz, 2H), 7.42 (t, J = 8.3 Hz, 2H), 7.30 (s, IH), 7.13 (s, IH), 4.23 (s, 2H), 3.40 (d, J = 13.0 Hz, IH), 1.99 (t, J = 13.0 Hz, 2H), 1.84 - 1.74 (m, 2H), 1.54 (d, J = 13.1 Hz, 2H), 1.46 - 1.36 (m, 2H). LCMS m/z 482.4 [M+H]⁺.

Compound 110

4-[6-(3-ethyloxetan-3-yl)-5-(4-fluorophenyl)-IH-pyrrolo[2,3-f] indazol- 7-yl] -3-fluoro-benzoic acid (110)

Compound 110 was prepared from Cl and 3-ethyl-3-ethynyl-oxetane in seven steps using the method described for the préparation of compounds 107 and 108. (2-fluoro-4390 methoxycarbonyl-phenyl)boronic acid was used in the Suzuki coupling step. (9.8 mg). ’h NMR (400 MHz, DMSO-rf₆) δ 12.61 (s, IH), 8.00 (s, IH), 7.81 (dd, J = 21.1, 9.1 Hz, 2H), 7.63 (s, 2H), 7.51 - 7.39 (m, 3H), 7.11 (s, IH), 7.01 (s, IH), 4.86 (d, J = 5.7 Hz, IH), 4.54 (d, J = 5.8 Hz, IH), 3.77 (dd, J = 16.1, 5.8 Hz, 2H), 2.12 - 2.01 (m, IH), 1.99 - 1.90 (m, IH), 1.03 (t, J = 7.3 5 Hz, 3H). LCMS m/z 474.2 [M+H]⁺.

Compound 111

4-[6-(3-ethyloxetan-3-yl)-5-(4-fluorophenyl)-lH-pyrrolo[2,3-f/indazol- 7-yl]benzoic acid (111)

Compound 111 was prepared from Cl and 3-ethyl-3-ethynyl-oxetane in seven steps using the method as described for the préparation of compounds 107 and 108. (4ethoxycarbonylphenyl)boronic acid was used in the Suzuki coupling step. Purification by reverse phase chromatography (Gradient: 0-100 % MeCN in water containing 0.1 % fonnîc acid) afforded the product (11.7 mg). 'H NMR (400 MHz, DMSO-ίή,) δ 13.01 (s, IH), 12.64 (s, IH),

8.08 (d, J = 7.8 Hz, 2H), 8.00 (s, IH), 7.66 - 7.60 (m, 2H), 7.57 (d, J = 7.9 Hz, 2H), 7.46 (t, J =

8.5 Hz, 2H), 7.34 (s, IH), 6.99 (s, IH), 4.60 (d, J = 5.5 Hz, 2H), 3.80 (d, J = 5.5 Hz, 2H), 2.08 (q, J = 7.0, 6.1 Hz, 2H), 1.11 (t, J = 7.4 Hz, 3H). LCMS m/z 456.2 [M+H]\

391

Compound112

4-[5-(4-fluorophenyl)-6-(2-methoxy-l,l-dimethyl-ethyl)-lH-pyrrolo[2,3-f] indazol- 7-yl] benzoic acid (112)

Step 1. Synthesis of ethyl 4-[l-(2,2-dimethylpropanoyl)-5-(4-fluorophenyl)-6-(2~methoxy-l,ldimethyl-ethyl)pyrrolo[2,3-fjindazol-7-yl]benzoate (Cil 1)

A solution of t-[5-(4-fluorophenyl)-7-iodo-6-(2-methoxy-l,l-dimethyl-ethyl)pyrrolo[2,3f]indazol-l-yI]-2,2-dimethyI-propan-l-one SU (5.7 g, 10.4 mmol), (4ethoxycarbonylphenyl)boronic acid (4 g, 20.6 mmol) and CsF (6.3 g, 41.5 mmol) in DME (120 10 mL) was purged with nitrogen. Pd(PPh₃)4 (1.2 g, 1.04 mmol) was added and the reaction mixture heated at reflux overnight. The mixture was concentrated and purified twice b y silica gel chromatography (Gradient: 0-60 % EtOAc in heptane). The product was dissolved în —100 mL of CFLCB: EtOAc (1:1) and then MP-TMT (1.6 g) scavenger resin was added. The mixture was stirred with the resin at room température overnight, and then filtered, and concentrated to afford 15 the product, which was used in the subséquent step without further purification (3.5 g, 59 %). ^lH NMR (300 MHz, Chlorofonmd) δ 8.21 - 8.12 (m, 2H), 8.10 (s, IH), 8.02 (d, J = 0.7 Hz, IH), 7.61 - 7.53 (m, 2H), 7.53 - 7.45 (m, 2H), 7.34 - 7.24 (m, 2H), 6.88 (d, J = 0.9 Hz, IH), 4.47 (q, J = 7.1 Hz, 2H), 3.08 (d, J = 2.2 Hz, 5H), 1.53 (s, 9H), 1.48 (t, J = 7.1 Hz, 3H), 1.17 (s, 6H). LCMS m/z 570.1 [M+H]⁺. Note: 1.3 g of de-iodinated SU was recovered in the reaction (33 %).

392

Step 2. Synthesis of 4-[5-(4fluorophenyl)-6-(2-methoxy-l,l-dimethyl-ethyl)-lH-pyrrolo[2,3J]indazol-7-yl]benzoic acid (112)

NaOH (1.32 mL of 1 M, 1.3 mmol) was added to a solution of ethyl 4-(1-(2,2dimethyIpropanoyl)-5-(4-fluorophenyl)-6-(2-methoxy-1,1 -dimethyl-ethyl)pyrrolo[2,3-f]mdazol7-yl]benzoate Cl 11 (125 mg, 0.2 mmol) in THF (2.5 mL) and MeOH (1.25 mL). The mixture was heated to 50 °C for 45 min. The mixture was concentrated in vacuo crude and minimal water was added. HCl (1.32 mL of 1 M, 1.32 mmol) was then added, to fonn a precipitate. Purification by reverse phase chromatography (Column: Cl S.Gradient: 10-100 % acetonitrile in water with 0.2% formic acid) afforded the product as a white crystalline solid. (100 mg, 100 %). 'H NMR (400 MHz, DMSO-rf₆) 5 12.91 (d, IH), 12.49 (s, IH), 8.10 - 8.05 (m, 2H), 7.96 (s, IH), 7.58 (t, J = 7.4 Hz, 4H), 7.52 - 7.46 (m, 2H), 6.83 (d, J = 7.4 Hz, 2H), 3.05 (s, 2H), 3.00 (s, 3H), 1.11 (s, 6H). LCMS m/z 458.4 [M+H]\

Compound 113-116

Compounds 113-116 were prepared in two steps from SU and the appropriate boronic ester or boronic acid via a Suzuki coupling followed by an ester hydrolysis, as described for the préparation of compound 112. Any modifications to these methods are noted in Table 9 and accompanying footnotes. In some ex amples, the Suzuki reaction was carried out in the presence of Pd₂(dba)j, SPhos, K3PO4, in THF-water at 60 °C. In some examples, the reaction was performed with XPhos Pd G3, K3PO4 in 1,4-dioxane-water at 60 °C.

Table 9. Method of préparation, structure, physicochemical data for compounds 113-116

Compound	Method /Product	Boronic acid or ester	'H NMR; LCMS m/z [M+H]”
113	Compound 112'1 from SU O. y-οπ A H / N r~ OMe àXX W··- F	O^O Me HO OH	'HNMR (400 MHz, DMSO-r/6) δ 13.33 (s, IH), 12.50 (s, IH), 7.98 (s, IH), 7.92 (d, J = 7.9 Hz, IH), 7.84 (d, J = 9.8 Hz, IH), 7.70 -7.60 (m, 2H), 7.58 7.45 (m, 3H), 6.83 (d, J = 10.1 Hz, 2H), 3.13-2.97 (m, 5H), 1.12 (s, 6H). LCMS m/z 476.2 [M+H] \

393

Compound	Method /Product	Boronic acid or ester	'HMIIZŒZ [M+H]+
114	Compound 11223from SU 0. V-OH F Γ rS H / N-yyZ /— OMe υΧΓζ F	O^O Me yzzx M hoboh	'H NMR (400 MHz, MethanolZ}) δ 8.03 (t, J = 7.9 Hz, IH), 7.93 (s, IH), 7.53 (dd, J = 8.1, 4.9 Hz, 2H), 7.41 -7.34 (m, 3H), 7.31 (d, J =11.6 Hz, IH), 6.98 (s, IH), 6.87 (s, IH), 3.17-3.09 (m, 5H), 1.18 (s, 6H). LCMS m/z 476.3 [M+H]+.
115	Compound 112l 3 from SU Οχ y-OH NZ MeO W H / N ZZZ OMe N 1 F	Ox^OMe N'y y \ MeO'^y y XA	'HNMR (400 MHz, Methanol-d4) δ 7.95 - 7.80 (m, 3H), 7.57 (dd, J = 8.6, 4.7 Hz, 1 H), 7.44 (dd,J = 8.7, 4.7 Hz, IH), 7.34 (q, .1 = 7.4 Hz, 2H), 6.83 (d, J = 6.9 Hz, 2H), 3.95 (s, 3H), 3.14-2.97 (m,5H), 1.13 (d, J = 4.8 Hz, 6H). LCMS m/z 489.4 [M+Hf.
116	Compound 1122 4from SU Οχ Z-OH N V y-y H / Ν-χΖΖΑ /—OMe ΑΓΗ' — Z^N 1 0 F	(V.OMe y z 0^	'H NMR (400 MHz, DMSO-d6)Ô 13.07 (s, IH), 12.48 (s, IH), 7.96 (s, IH), 7.84 (d,J = 7.4 Hz, IH), 7.78 (d, J = 7.3 Hz, IH), 7.65 - 7.58 (m, IH), 7.56 7.45 (m, 3H), 6.80 (d, J = 11.2 Hz, 2H), 5.29 (p, J = 7.2 Hz, 1 H), 3.05 (s, 2H), 2.98 (s, 3H), 2.47 -2.39 (m, 1 H), 2.38 -2.29 (m, IH), 1.92 (p, J = 9.9 Hz, 2H), 1.75 - 1.54 (m, 2H), 1.14 (s, 6H). LCMS m/z 529.3

* Pd₂dba₃, K₃PO₄, SPhos, THF-water, 60 °C ¹ XPhos Pd G3, K₃PO₄, 1,4-dioxane-water, 60 °C

394 ³· Purification by reversed-phase chromatography (Column: C18. Gradient: 10-100% MeCN in water with 0.2 % fonnic acid) afforded the product.

⁴' Purification by reversed-phase chromatography (Column: C18. Gradient: 0-100 % MeCN in water with 0.1 % trifluoroacetic acid) afforded the product.

Compound 117

4-[5-(4-fluorophenyl)-6-[l-(methoxymethyl)cyclobutyl]-lH~pyrrolo[2,3-f]indazol-7-yl]benzoic acid (117)

Step 1. Synthesis of methyl 4-[2-[ 1 -[[tert-butyl(dimethyl)silyl] oxymethyl] cyclobutyl] ethynyl] benzoate (Cl 13)

A solution of methyl 4-iodobenzoate (330 mg, 1.26 mmol) in DMF (1.9 mL) was purged with nitrogen for 10 min. Tert-butyl-[(l-ethynylcyclobutyl)methoxy]-dimethyl-silane Cl 12 (366 mg, 1.63 mmol), diethylamine (405 pL, 3.9 mmol) were added, followed by PdCl₂(PPh₃)2 (45.9 15 mg, 0.07 mmol) and Cul (18.1 mg, 0.10 mmol). The mixture was heated at 90°C for 90 min under a nitrogen atmosphère. The mixture was then concentrated to dryness, and followed by

395 partitioning between CH^CL and water. The organic layer was passed through a phase separator and concentrated in vacuo. Purification by silica gel chromatography (Gradient: 0-100 % EtOAc in heptane) afforded the product (423 mg, 92 %). LCMS m/z 359.2 [M+H]^h.

(Cl 12 was synthesized according to the method described by Chen, G., Zhang, X., Wei, Y., Tang. X. and Shi, M. (2014), Catalyst J Dépendent Divergent Synthesis of Pyrroles from 3j Alkynyl Imine Derivatives: A Noncarbonylative and Carbonylative Approach. Angew. Chem. Int. Ed., 53: 8492-8497).

Step 2. Synthesis of methyl 4-[2-[l-(hydroxymethyl)cyclobutyl] ethynyl]benzoate (Cl 14)

To solution of methyl 4-[2-[ 1 -[[tertbutyl(dimethyl)silyl]oxymethyl]cyclobutyl]ethynyl]benzoate Cl 13 (150 mgs) in THF (13.6 mL) was added TBAF (410 pL of 1 M, 0.41 mmol). The reaction mixture was stirred at room température for 2 h then concentrated in vacuo. The mixture was then partîtioned between CH₂CL and water. The organic layer was passed through a phase separator, and then concentrated in vacuo to afford the product (60 mg, 59 %). LCMS m/z 245.1 [M+H]\ Step 3. Synthesis of methyl 4-[2-[l-(methoxymethyl)cyclobutyl]ethynyl]benzoate (Cl 15) A solution of methyl 4-[2-[l-(hydroxymethyI)cyclobutyl]ethynyl]benzoate Cl 14 (90 mg, 0.36 mmol) in THF (1.0 mL) was cooled to 0 °C. Sodium hydride (8.6 mg, 0.36 mmol) and methyl iodide (22.5 pL, 0.36 mmol) were added. The reaction mixture was stirred at room température for 2 h. Further methyl iodide (22.5 pL, 0.36 mmol) and sodium hydride (8.6 mg, 0.36 mmol) were added and the reaction stirred at room température for an additional 2 h. The mixture was partîtioned between CH₂C1₂ and water. The organic layer was passed through a phase separator and concentrated in vacuo. Purification by silica gel chromatography (Eluent: 0-100 % EtOAc in heptane) afforded the product (423 mg, 92 %). LCMS m/z 259.1 [M+H]⁺.

Step 4. Synthesis o] 6-bromo-N-(4-fluorophenyl)-lH-indazol-5-amine (Cl 17)

A solution of 1-fluoro-4-iodo-benzene (1.6 mL, 13.9 mmol), 6-bromo-lH-indazol-5amîne C116 (2000 mg, 9.4 mmol), NaOtBu (3.9 g, 40.1 mmol), and tBuXPhos Pd G4 (432 mg, 0.48 mmol) in tBuOH (50 mL) was degassed with nitrogen, then allowed to stir at room température for 5 h. The mixture was diluted with EtOAc, washed with saturated sodium bicarbonate solution and then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (Gradient: 0-100 % EtOAc in heptane) afforded the product (1.8 g, 62 %). ^lH NMR (400 MHz, DMSO) δ 13.06 (s, IH), 7.99 (s, IH), 7.89 (s, IH), 7.59 (s, IH), 7.48 (d, J = 1.7 Hz, IH), 7.09 - 6.88 (m, 2H), 6.80 (dd, J = 8.1,4.7 Hz, 2H). LCMS m/z 305.1 [M+H]⁺.

Step 5. Synthesis of l-[6-bromo-5-(4-fluoroanilino)indazol-l-yl]-2,2-dimethyl-propan-l-one (C118)

396

To a suspension of 6-bromo-N-(4-fluorophenyl)-lH-indazol-5-amine Cl 17 (754 mg, 2.46 mmol) in THF (15 mL) at 1 °C (ice-water bath) was added KOtBu (2.6 mL of 1 M, 2.6 mmol). After 10 min, 2,2-dimethylpropanoyl chloride (965 pL, 7.84 mmol) was added.The reaction was stirred for 30 min in cooling bath. Further 2,2-dimethylpropanoyl chloride (25 pL) was added and the mixture stirred for an additional 30 min. The reaction was quenched with water (3 mL), and stirred for 5 min, then concentrated under reduced pressure. The mixture was partitioned between CH₂C1₂ (20 mL) and water (10 mL). The organic layer was passed through a phase separator and concentrated in vacuo to afford product. (971 mg, 100 %). ^!H NMR (300 MHz, DMSO-t/é) 5 8.61 - 8.56 (m, IH), 8.36 (d, J = 0.9 Hz, IH), 7.62 (s, IH), 7.57 (s, IH), 7.16 - 7.04 (m, 4H), 1.49 (s, 9H). LCMS m/z 390.2 [M+H]⁺.

Step 6: Synthesis of methyl 4-[l-(2,2-dimethylpropanoyl)-5-(4-jluorophenyl)-6~[l(methoxymeihyl)cyclobutyl]pyrrolo[2,3-J] indazol-7-yl]benzoate (C119) l-[6-bromo-5-(4-fluoroanilino)mdazoI-l-yl]-2,2-dimethyl-propan-l-one C118 (40 mg, 0.10 mmol), methyl 4-[2-[l-(methoxymethyl)cyclobutyl]ethynyl]benzoate (39.2 mg, 0.15 mmol) and Pd(PtBu₃)₄ (2.5 mg, 0.005 mmol) were combined in a vial under a nitrogen atmosphère. 1,4-dioxane (506 pL) and N-cyclohexyl-N-methyl-cyclohexanamine (54.1 pL, 0.25 mmol) were added. The réaction mixture was then stirred at 110 °C for 1 h. The reaction was quenched with NH4CI and partitioned between CH₂C1₂ and water. The organic layer was passed through a phase separator and concentrated in vacuo. Purification by silica gel chromatography (Gradient: 0-30 % EtOAc in heptane) afforded the product (27 mg, 44 %). “H NMR (300 MHz, DMSO-î/₆) Ô 8.61 - 8.56 (m, IH), 8.36 (d, J = 0.9 Hz, IH), 7.62 (s, IH), 7.57 (s, IH), 7.16 - 7.04 (m, 4H), 1.49 (s, 9H). LCMS m/z 568.2 [M+H]¹’.

Step 7. Synthesis o] 4-[5-(4-fluorophenyl)-6-[l-(methoxymethyl)cyclobutyl]-lH~pyrrolo[2,3f] indazol-7-yl] benzoic acid (117)

NaOH (215 pL of 1 M, 0.22 mmol) was added to a solution of methyl 4-(1-(2,2dimethyIpropanoyl)-5-(4-fluorophenyl)-6-[l-(methoxymethyl)cyclobutyl]pyrrolo[2,3-f]indazol7-yI]benzoate C119 (27 mg, 0.05 mmol) m THF (611 pL) and MeOH (252 pL). The reaction mixture was allowed to stir at 50 °C for 30 min, and then concentrated under reduced pressure. Purification by reverse phase column chromatography (Eluent: MeCN in water with 0.1 % formic acid modifier) afforded the desired product (8.5 mg, 37 %). *H NMR (400 MHz, DMSOd_b) δ 13.00 (s, iH), 12.58 (s, IH), 8.05 - 7.95 (m, 3H), 7.79 (d, J = 7.8 Hz, 2H), 7.65 - 7.58 (m, 2H), 7.44 (t, J = 8.4 Hz, 2H), 7.32 (s, IH), 6.91 (s, IH), 3.71 (s, 2H), 3.36 (s, 3H), 2.08 (q, J = 9.8 Hz, 2H), 1.55 - 1.43 (m, 4H). LCMS m/z 470.2 [M+H]T

397

Compound 118

4-/5-(4-fluoropheny 1)-6-/l-(hydroxymethyl)cyclobutyl/ -1 H-pyrro lo[2,3-fl indazol- 7-yl] benzo ic

acid (118)

Step 1. Synthesis of 4-/6-/1 -[/tert-butyl(dimethyl)silyl] oxymethyl]cyclobutyl]-!-(2,2dimethylpropanoyl)-5-(4-fluorophenyl)pyrrolo/2,3-f] indazol-7-yl]benzoate (C120)

To a mixture of l-[6-bromo-5-(4-fluoroamlino)indazol-l-yl]-2,2-dimethyl-propan-l-one

Cl 18 (60 mg, 0.15 mmol), methyl 4-[2-[ 1 -[[tertio butyl(dimethyl)silyl]oxymethyl]cyclobutyl]ethynyl]benzoate (93 mg, 0.26 mmol) (C113), and Pd(/Bu₃P)2 (3.8 mg, 0.007 mmol), under a nitrogen atmosphère, was added 1,4-dioxane (760 pL) and N-cyclohexyl-N-methyl-cyclohexanamine (81.4 pL, 0.3 mmol). The mixture was allowed to stir at 110 °C for 1 h. The reaction was quenched with NH₄C1 and partitioned between CHiCb and water. The organic layer was passed through a phase separator and concentrated in vacuo.

Purification by silica gel chromatography (Gradient: 0-30 % EtOAc în heptane) afforded the product (124 mg, 33 %). LCMS m/z 668.2 [M+H]⁺.

398

Step 2: Synthesis of 4-[l-(2,2-dimethylpropanoyl)-5-(4-fluorophenyl)-6-[l(hydroxymethyl)cyclobutyl]pyrrolo[2,3-flindazol-7-yl] benzoate (C121)

TBAF (185 pL of l M, 0.19 mmol) was added to a solution of methyl 4-[6-[l -[[tertbutyl(dimethyl)silyl]oxymethyl]cyclobutyl]-l-(2,2-dimethylpropanoyl)-5-(45 fluorophenyl)pyrrolo[2,3-f]indazol-7-yl]benzoate C120 (124 mg, 0.19 mmol) in THF (6.1 mL). The reaction mixture was allowed to stir at room température for 2 h. The mixture was partitioned between CH2CI2 and water. Tire organic layer was passed through a phase separator and concentrated to in vacuo to afford the product (97 mg, 94 %). LCMS m/z 554.2 [M+H] / Step 3: 4-[5-(4-fluorophenyl)-6-[I-(hydroxymethyl)cyclobutyl] -IH-pyrro lo[2,3-flindazol-710 yljbenzoic acid (118)

NaOH (221 pL of 1 M, 0.22 mmol) was added to a solution of methyl 4-[ 1-(2,2dimethylpropanoyl)-5-(4-fluorophen yl)-6-[1-(h ydroxymethyl)cy cl obutyl]pyrrolo [2,3-f| indazol7-yl]benzoate (27 mg, 0.05 mmol) in THF (611 pL) and MeOH (252 pL). The reaction mixture was stirred at 50 °C for 30 min, and then concentrated in vacuo. Purification by reverse phase 15 column chromatography (Eluent: MeCN in water with 0.1 % formic acid modifier) afforded the product (8.2 mg, 35 %). ‘H NMR (400 MHz, DMSOA) δ 12.97 (s, IH), 12.57 (s, IH), 8.03 7.96 (m, 3H), 7,87 (d, J = 7.5 Hz, 2H), 7.70 - 7.63 (m, 2H), 7.43 (t, J = 8.2 Hz, 2H), 7.35 (s, IH), 6.89 (s, IH), 5.34 - 5.26 (m, IH), 3.81 (d, J = 4.5 Hz, 2H), 2.09 - 1.98 (m, 2H), 1.55 - 1.44 (m, 4H). LCMS m/z 456.1 [M+H]⁺.

399

Compound 119

4-[5.(4-fluorophenyl)-6-(2-hydroxy-1,1 -dimelhyl-ethyl)-lH-pyrrolo[2,3-f] indazol- 7-yl]benzoic acid (119)

C122 C123

Step 1.Synthesis of methyl 4-(4-hydroxy-3,3-dimethyl-but-I-ynyl)benzoate (Cl23)

A solution of 2,2-dimethylbut-3-yn-l-ol C122 (1 g, 10.2 mmol) and methy] 4iodobenzoate (4.0 g, 15.3 mmol) in NEt₃ (10 mL) and 1,4-dioxane (10 mL) was degassed and purged with nitrogen. Cul (194 mg, 1.0 mmol) and Pd(PPh₃)₂Cl₂ (453 mg, 0.65 mmol) were added, and the reaction stirred under a nitrogen atmosphère at 90 °C for 2 h. The mixture was

400 concentrated to dryness under reduced pressure and partitioned between CH2CI2 and water. The organic layer was passed through a phase separator and concentrated to dryness under reduced pressure. Purification by silica gel chromatography (Gradient: 0-100% EtOAc in heptane) afforded the product (1.49 g, 58 %). ^!H NMR (400 MHz, Chloroform-d) δ 8.02 - 7.95 (m, 2H), 7.51 - 7.46 (m, 2H), 3.94 (s, 3H), 3.54 (d, J = 6.9 Hz, 2H), 1.34 (s, 6H). LCMS m/z 233.1 [M+H]Ê

Step 2. 4-[l-(2,2-dimethylpropanoyl)-5-(4-fluorophenyl)-6-(2-hydroxy-l, 1-dimethylethyl)pyrrolo[2,3-f] indazol- 7-yl] benzoate (C124)

To a mixture of l-[6-bromo-5-(4-fluoroanilino)indazol-l-yl]-2,2-dimethyl-propan-l-one (80 mg, 0.21 mmol) C118, methyl 4-(4-hydroxy-3,3-dimethyl-but-l~ynyl)benzoate (71 mg, 0.31 mmol) and Pd(iBu₃P)₂ (5.1 mg, 0.01 mmol) under a nitrogen atmosphère was added 1,4-dioxane (1.0 mL), followed by N-cyclohexyl-N-methyl-cyclohexanamine (109 pL, 0.51 mmol). The mixture was stirred at 100 °C for 1 h. The reaction was then quenched with NH₄C1 and partitioned between CH2CI2 and water. The organic layer was passed through a phase separator and concentrated to dryness in vacuo. Purification by silica gel chromatography (Eluent: ΟΙ 00 % EtOAc in heptane) afforded the product (124 mg, 33 %). LCMS m/z 542.1 [M+H]⁺. Step 3. 4-[5-(4-fluorophenyl)-6-[ 1 -(hydroxymethyl)cyclobutyl/-ÎH-pyrrolo[2,3-f]indazol-7yl] benzoic acid (119)

NaOH (226 pL of 1 M, 0.23 mmol) was added to a solution of 4-[ 1-(2,2dimethylpropanoyl)-5-(4-fluorophenyl)-6-(2-hydroxy-1,1 -dimethyl-ethyl )pyrrolo[ 2,3-f] indazol 7-yl]benzoate C124 (30 mg, 0.05 mmol) in THF (609 pL) and MeOH (252 pL). The mixture was stirred at 50 °C for 30 min then concentrated under reduced pressure. Purification by reverse phase column chromatography (Eluent: MeCN in water with 0.1 % formic acid modifier) afforded the product. (15.0 mg, 64 %). ^lH NMR (400 MHz, DMSO-J₆) δ 12.99 (s, IH), 12.47 (s, IH), 8.06 (d, J = 7.6 Hz, 2H), 7.96 (s, IH), 7.66 - 7.57 (m, 4H), 7.47 (t, J = 8.3 Hz, 2H), 6.82 (d, J = 12.9 Hz, 2H), 4.79 (t, J = 5.4 Hz, IH), 3.31 (s, 2H), 1.02 (s, 6H). LCMS m/z 444.1 [M+H]⁺.

Compound120

5-[4-f5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3-f]indazol-7yl] phenyl] imidazolidine-2,4-dione (120)

401

120 F

Synthesis of 5-[4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3-f]indazol- 7yl]phenyl]imidazolidine-2,4-dione (120)

A solution of Na₂CO3 (225 pL of 2 M, 0.5 mmol) was added to a solution of l-[5-(4fluorophenyl)-7-iodo-6-tetrahydropyran-4-yI-pyrrolo[2,3-f]indazol-l-yl]-2,2-dimethyl-propan-lone S4 (100 mg, 0.18 mmol), [4-(2,5-dioxoimidazolidin-4-yl)phenyI]boronic acid (50 mg, 0.23 mmol), and Pd(PPh3)₄ (10 mg, 0.009 mmol) were dissolved in 1,4-dioxane (750 pL) and DMF (750 pL). The mixture was stirred at 100 °C for 24 h, and then partitioned between CH₂C1₂ and water. The organic layer was passed through a phase separator and concentrated to dryness under reduced pressure. Purification by reversed-phase HPLC (Column: Cl 8 Waters Sunfire column 30 xl50 mm, 5 micron. Gradient: 10-100% MeCN in H₂O with 0.1 % TFA) afforded the product (3.2 mg, 3 %). ^lH NMR (400 MHz, DMSO-rf₆) δ 12.55 (s, IH), 10.89 (s, IH), 8.51 (s, IH), 8.00 (s, IH), 7.63 (dd, J = 8.7, 5.0 Hz, 2H), 7.58 - 7.47 (m, 6H), 7.20 (s, IH), 7.07 (s, IH), 5.31 (s, IH), 3.73 (d, J = 11.0 Hz, 2H, overlap from solvent), 3.17-3.04 (m, 2H), 3.01 - 2.93 (m, IH), 1.67 (s, 4H). LCMS m/z 510.2 [M+H]⁺.

Compound 121

5-(4-fluorophenyl)-7-(6-methylsidfonyl-3-pyridyl)-6-tetrahydropyran-4-yl-1 H-pyrrolo [2,3fjindazole (121)

402

5-(4 -fluorophenyl)-7- (6-methylsulfonyl-3-pyridyl)-6~tetrahydropyran-4-yl-lH-pyrrolo[2,3fjindazole (121)

A solution of Na₂CO₃ (450 pL of 2 M, 0.9 mmol) was added to a solution of 1-(5-(4fluorophenyl)-7-iodo-6-tetrahydropyran-4-yl-pyrrolo[2,3-f]indazol-l-yl]-2,2-dimethyI-propan-l5 one S4 (200 mg, 0.36 mmol), (6-methylsulfonyl-3-pyridyI)boronic acid (88 mg, 0.44 mmol), and Pd(PPh₃)₄ (21 mg, 0.018 mmol) in 1,4-dioxane (1.5 mL) and DMF (1.5 mL). The reaction was stirred at 160 °C for 1 h, then partitioned between CH₂C1₂ and water. The organic layer was passed through a phase separator, and concentrated to dryness in vacuo. Purification by reverse phase column chromatography (Gradient: 0-40 % acetonitrile in water with fonnic acid modifier) afforded the product (69 mg, 39 %). ^!H NMR (400 MHz, DMSO-ri₆) Ô 12.66 (s, IH), 8.95 (dd, J = 2.2, 0.8 Hz, IH), 8.31 (dd, J = 8.1, 2.2 Hz, IH), 8.23 (dd, J = 8.1, 0.8 Hz, IH), 8.03 (t, J= 1.3 Hz, IH), 7.70- 7.60 (m, 2H), 7.53 (t, J = 8.7 Hz, 2H), 7.31 (t, J = 1.1 Hz, IH), 7.11 (d, J = 0.9 Hz, IH), 3.75 (dd, J = 11.3, 4.0 Hz, 2H), 3.41 (s, 3H), 3.14 (t, J = 11.4 Hz, 2H), 3.02 (m, l H), 1.72 (d, J = 12.6 Hz, 2H), 1.63 (m, 2H). LCMS m/z 491.1 [M+H]⁺.

Compound 122

4-[5-(4-fluorophenyl)-6-(2-methoxy-2-methyl-propyl)-lH-pyrrolo[2,3-f] indazol- 7-yl]benzoic acid (122)

403

NaOH

Step 1. Synthesis of 6-bromo-5-chloro-l-tetrahydropyran-2-yl~indazole (Cl25)

To a suspension of 6-bromo-5-chloro-lH-indazole C6 (25 g, 100.4 mmol) and 3,4dihydro-2H-pyran (28 mL, 306.9 mmol) in CH2CI2 (300 mL) was added 45 methyIbenzenesulfonic acid monohydrate (1.8 g, 9.46 mmol). The reaction was allowed to stir at °C for 1 h. The reaction was washed with NaHCO₃ and extracted with dichloromethane (x 3). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography (Eluent: 0-30 % EtOAc in heptane) afforded the product (30.8 g, 97 %). 'H NMR (300 MHz, Chlorofonn-d) δ 7.87 (d, J = 0.8 Hz, 2H), 7.76 (s, IH), 5.59 (dd, J = 10 9.1, 2.6 Hz, IH), 4.08 - 3.86 (m, IH), 3.77 - 3.49 (m, IH), 2.52 - 2.29 (m, IH), 2.04 (m, 2H),

1.82 - 1.53 (m,3H). LCMS m/z 315.0 [M+H]’.

Step 2. 5-(5-chloro-l-tetrahydropyran-2-yl-indazol-6-yl)-2-methyl-pent-4-yn-2-ol (C126)

404

To a solution of 6-bromo-5-chloro-l-tetrahydropyran-2-yl-indazole C125 (400 mg, 1.27 mmol), 2-methylpent-4-yn-2-ol (124 mg, 1.26 mmol), and Et₃N (3.3 mL) in 1,4-dioxane (3.2 mL) was purged with nitrogen. Cul (24.1 mg, 0.13 mmol) and Pd(PPh₃)₂Cl₂ (56mg, 0.08 mmol) were added and the reaction was stirred at 100 °C for 1 h. The mixture was partitioned between CH₂C1₂ and water. The organic layer was passed through a phase separator and concentrated to dryness under reduced pressure. Purification by silica gel chromatography (Eluent: 0-100% EtOAc in heptane) afforded the product (264 mg, 59 %). *H NMR (400 MHz, Chlorofonn-d) δ 7.94 (d, J = 0.7 Hz, IH), 7.75 (s, 2H), 5.67 (dd, J = 9.3, 2.7 Hz, IH), 4.06 - 3.99 (m, IH), 2.69 (s, 2H), 2.56-2.45 (m, IH), 2.18-2.03 (m, 3H), 1.80- 1.61 (m, 3H), 1.43 (s, 6H). LCMS m/z 333.1 [M+H]⁺.

Step 3. Synthesis of 5-chloro-6-(4-methoxy-4-methyl-pent-l-ynyl)-l-tetrahydropyran-2-ylindazole (Cl 27)

To a solution of 5-(5-chloro-l-tetrahydropyran-2-yl-indazol-6-yl)-2-methyl-pent-4-yn-201 Cl26 (720 mg, 2.0 mmol) in THF (9.7 mL) at 0 °C was added NaH (135 mg of 60 % w/w, 3.38 mmol). The reaction was warmed to room température and stirred for 1 h. Upon cooling to 0 °C, methyl iodîde (187 pL, 3.0 mmol) was added. The reaction was warmed to room température, and stirred for 1 h. Additional NaH (135 mg of 60 %w/w, 3.34 mmol) was added. The mixture was stirred for 1 h, and then further methyl iodide (187 pL, 3.0 mmol) was added. The reaction mixture was partitioned between CH?C1₂ and water. The organic layer was passed through a phase separator and concentrated to dryness under reduced pressure. Purification by silica gel chromatography (Eluent: 0-100 % EtOAc in heptane) afforded the product (566 mg, 81 %). LCMS m/z 347.1 [M+H]⁺.

Step 4. Synthesis of N-(4-fluorophenyi)-6-(4-methoxy-4-methyl-pent-l -ynyl)-1 -tetrahydropyran2-yl-indazol-5-amine (C128)

A solution of chloro-6-(4-methoxy-4~methyl-pent-l-ynyl)-l-ietrahydropyran-2-ylindazole C127 (566 mg, 1.63 mmol), NaOtBu (465 mg, 4.84 mmol), and 4-fluoroaniline (271 mg, 2.44 mmol) in tBuOH (7.3 mL) was degassed with nitrogen for 10 min, tBuXPhos Pd G1 (154 mg, 0.17 mmol) was added. The reaction mixture was stirred at 90 °C for 1 h, and then partitioned between CH₂CI₂ and water. The organic layer was passed through a phase separator and concentrated to dryness under reduced pressure. Purification by silica gel chromatography (Eluent: 0-100 % EtOAc in heptane) afforded the product (530 mg, 77 %). LCMS m/z 422.2 [M+Hf.

Step 5. Synthesis of 5-(4-fluorophenyl)-6-(2~methoxy-2-methyl-propyl)-l-tetrahydropyran~2-vT pyrrolo[2,3-f] indazole (C129)

405

A mixture of N-(4-fluorophenyl)-6-(4-methoxy-4-methyl-pent-l-ynyl)-Itetrahydropyran-2-yl-indazol-5-amine CJ28 (530 mg, 1.26 mmol), tris(4fluorophenyl)phosphane (92.8 mg, 0.3 mmol), and [Rh(COD)Cl]₂ (29.3 mg, 0.06 mmol) was purged with nitrogen for 10 min. DMF (5.3 mL) was added and the solution was degassed. The reaction was then allowed to stirred at 100 °C for 24 h, then partitioned between CH₂Cl₂ and water. The organic layer was passed through a phase separator and concentrated to dryness under reduced pressure. Purification by silica gel chromatography (Eluent: 0-100% EtOAc in heptane) afforded the product (314 mg, 59 %). LCMS m/z 422.2 [M+H]⁺.

Step 6. Synthesis of 5-(4-fluorophenyl)-6-(2-methoxy-2-methyl-propyl)-lH-pyrrolo[2,3]]indazote (Cl30)

To a solution of 5-(4-fluorophenyl)-6-(2-methoxy-2-methyl-propyI)-1 -tetrahydropyran-2yl-pyrrolo[2,3-f]indazole C129 (314 mg, 0.75 mmol) in MeOH (3.1 mL), EtOAc (3.1 mL) and H₂O (1.5 mL) was added 4-methylbenzenesulfonic acid monohydrate (638 pL, 3.6 mmol). The reaction was stirred at 50 °C for 1 h, then partitioned between CH₂C1₂ and saturated sodium bicarbonate. The organic layer was passed through a phase separator and concentrated to dryness under reduced pressure to afford the product (265 mg, 106 %). LCMS m/z 33 8.1 [M+H]⁺. Step 7. Synthesis of l-[5-(4-fhiorophenyl)-6-(2-methoxy-2-methyl-propyi)pyrrolo[2,3f]indazol1 -yl]-2,2-dimethyl-propan-l -one (C131)

To a solution of 5-(4-fluorophenyI)-6-(2-methoxy-2-methyl-propyl)-l H-pyn'olo[2,3f]indazole C130 (233 mg, 0.69 mmol) in THF (5.2 mL) at 0 °C was added KOtBu (171 mg, 1.5 mmol). After stirring for 10 min, 2,2-dimethylpropanoyl chloride (329 pL, 2.67 mmol) was added and the réaction stirred at 0 °C for I h. Purification by silica gel chromatography (Gradient: 0-100 % EtOAc in heptane) afforded the product (231 mg, 56 %). LCMS m/z 422.2 [Μ+ΗΓ.

Step 8. Synthesis of l-]5-(4-fluorophenyl)-7-iodo-6-(2-methoxy-2-methyl-propyl)pyrrolo[2,3f]indazol- } -yl]-2,2-dimethyl-propan-1 -one (Cl32) l-iodopyrrolidine-2,5-dione (118 mg, 0.5 mmol) was added portion-wise to a solution of l-[5-(4-fluorophenyl)-6-(2-methoxy-2-methyl-propyl)pyrrolo[2,3-f]indazol-l-yl]-2,2-dim ethylpropan-l-one C131 (231 mg, 0.38 mmol) in CH₂C1₂ (1.6 mL) at 0 °C. The reaction mixture was stirred for 1 h at 0 °C. The mixture was then washed with Na₂SO₃ (IM). The organic layer was passed through a phase separator and concentrated in vacuo to afford the product (165 mg, 79 %). LCMS m/z 548.1 [M+H]⁺.

Step 9. Synthesis of ethyl 4-]l-(2,2-dimethylpropanoyl)-5-(4-fluorophenyl)-6-(2-methoxy-2methyl-propyl)pyrrolo[2,3-f]indazol-7-yl]benzoate (Cl33)

406 l-[5-(4-fluorophenyl)-7-iodo-6-(2-methoxy-2-methyl-propyl)pyiTolo[2_}3-f]indazoî-l-yl]2,2-dimethyl-propan-1-one C132 (50 mg, 0.09 mmol), (4-ethoxycarbonyIphenyl)boronîc acid (34.9 mg, 0.18 mmol) and Pd(dppf)C12 (3.4 mg, 0.004 mmol) were combined in a flask and purged with nitrogen. 1,4-dioxane (302 pL) and sodium carbonate (139 pL of 2 M, 0.28 mmol) were added and the reaction stirred at 95 °C for 1 h. The reaction mixture was then partîtioned between CH2CI2 and water. Organic layer was passed through a phase separator and concentrated to dryness under reduced pressure. Purification by silica gel chromatography (Eluent: 0-100% EtOAc in heptane) afforded the product (16 mg, 17%). LCMS m/z 570.2 [M+H]⁺.

Step 10. Synthesis oj 4-[5-(4-fluorophenyl)-6-(2-methoxy-2-methyl-propyl)-lH-pyrrolo[2,3f] indazol-7-yl] benzoic acid (122)

To a solution of ethyl 4-[ 1-(2,2-dimethylpropanoyl)-5-(4-fluorophenyl)-6-(2-methoxy-2m ethy l-propyl)pyrrolo[2,3-f] indazol-7-yl]benzoate C133 (12 mg, 0.019 mmol), in THF (244 pL) and MeOH (101 pL) was added NaOH (86.0 pL of 1 M, 0.09 mmol). The reaction mixture was stirred at 50 °C for 30 min. The solvent was concentrated to dryness under reduced pressure. Purification by reverse phase column chromatography (Gradient: MeCN in water with 0.1 % fonnic acid modifier) afforded the desired product (5.5 mg, 62 %). 'H NMR (400 MHz, DMSO40 δ 13.01 (s, IH), 12.64 (s, IH), 8.10 (d, J = 7.8 Hz, 2H), 8.03 (s, IH), 7.73 (d, J = 7.9 Hz, 2H), 7.62 - 7.56 (m, 2H), 7.53 - 7.45 (m, 3H), 7.33 (s, IH), 3.15 (s, 2H), 2.69 (s, 3H), 0.67 (s, 6H). (16 mg, 17 %). LCMS m/z 458.2 [M+Hf.

Compound 123

4-(5-(4-fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl-3,3,4,5,5-d5)-l,5-dihydropyrrolo[2,3]] indazol-7-yljbenzoic acid (123)

II D2O d 0---“ V 2. NaBD4 D2O C134 C MgBr ™S X n ™S____. D'd D CofacacL L J TMEDA 0

imidazole □ ' d ------d4dJp g 135 C136

407

C138 ^C139

C141

Step 1. Synthesis ofTetrahydro-2H-pyran-3,3,4,5,5-dfl-ol (C135)

Tetrahydro-4/Z-pyran-4-one Cl34 (50,0 g, 499 mmol) was dissolved in D₂O (1 L, 99.8 %

D) and K₂CO₃ (6.90 g, 49.9 mmol) was added. The mixture was stirred for 21 h and the obtained 5 solution was used as such in the next step. ^]H NMR (300 MHz, D₂O) Ô 4.05 (s, 3 H), 3.78 (s, IH).

NaBD₄ (6,27 g, 150 mmol) was added portion-wise over 15 min to a solution of tetrahydro-4H-pyran-4-one-3,3,5,5-î/4 (52.0 g, 499 mmol) in D₂O (1 L) at 10 °C. The mixture

408 was stirred for I h at room température. The mixture was then quenched with 35 % DCI in D₂O (20 mL) and concentrated. The residue was dissolved in CH₂Cl₂ (300 mL), dried over Na₂SO₄, filtered (sintered glass filter; washed with CH₂Cl₂) and concentrated to afford the product as a pale-yellow oil which was used in the subséquent step without further purification (46 g, 86 % yield). 'H NMR (300 MHz, CDCfi) δ 3.95 (d, J= 11.7 Hz, 1 H), 3.43 (d, J= 11.8 Hz, IH). Step 2. Synthesis of 4-Iodotetrahydro-2H-pyran-3,3,4,5,5-ds (C136).

Tetrahydro-2J7-pyran-3,3,4,5,5-^-4-01 Cl35 (92.7 g, 865.1 mmol) was dissolved in CH₂C1₂ (1.5 L) and PPI13 (249.6 g, 951.6 mmol) and 1/7-imidazole (64.8 g, 951.6 mmol) were added (clear pale-yellow solution). The mixture was cooled to 0 °C. I₂ (230.5 g, 908.3 mmol) was added in 8 portions at 0 °C over 1 h (orange suspension). The reaction mixture was stirred ovemight. It was quenched with H₂O and the phases were separated. The organic phase was washed with 10 % Na₂S₂O5 (2 ^x 200 mL), H₂O (200 mL), dried over Na₂SO₄ and concentrated. The pale-yellow solid residue was purified by distillation (liquid product trapped în the solids, which melted at high températures). The product distilled ai 70-77 °C to afford the product as a coloriess liquid (110.7 g, 59 % yield), 'HNMR (300 MHz, CDC1₃) δ 3.81 (d, J= 11.8 Hz, IH), 3.51 (d, J= 11.6 Hz, IH).

Step 3. Synthesis ofTrimethyl((tetrahydro-2H-pyran-4-yl-3,3,4,5,5-ds)ethynyl)silane (Cl37)

Ethynyltrimethylsilane (3 L0 g, 44.6 mL, 315.6 mmol) was dissolved in THF (250 mL) and EtMgBr (3 M, 40.0 g, 99.9 mL, 299.8 mmol) was added slowly drop-wise while being cooled in a water bath. The reaction mixture was heated at 50 °C for 1 h which afforded a brown solution. To a flask containing 4-iodotetrahydro-2/7-pyran-3_!3,4,5,5-d'5 C136 (41.0 g, 188.9 mmol) in THF (100 mL) cooled on an ice-water bath, was added TMEDA (32.9 g, 42.4 mL, 283.3 mmol) and cobalt(lll) (2)-4-oxopent-2-en-2-olate (7.4 g, 20.8 mmol). ((Trimethylsilyl)ethynyl)-magnesium bromide (60.9 g, 302.2 mmol, still at - 50 °C) was added drop-wise over 20 min while the mixture was cooled în an ice-water bath. The cooling bath was removed and the reaction mixture was stirred for 3 h at room température. The mixture was quenched with IM aq. citric acid (300 mL) while being cooled in an ice bath. TBME was added and the phases were separated. The organic phase was washed with IM aq. citric acid (200 mL) and brine, dried over Na₂SO₄, filtered, and concentrated to a black oil containing some solids (48.3 g). The crude was dissolved in CH₂C1₂ and stirred with charcoal for l h. The mixture was filtered through a Celite® plug, washed with CH₂C1₂ (x 4), and concentrated to give a black oil (43.77 g). Purification by distillation (Heating at 125-150 °C; vapor température at 72-84 °C; pressure at 17-21 mbar) afforded the product as a yellow oil: 21.6 g (61 % yield) J H NMR (300 MHz, CDC1₃) δ 3.87 (d, J= 11.6 Hz, IH), 3.47 (d, 11.6 Hz, IH), 0.15 (s, 5H).

409

Step 4. Synthesis of 5-Bromo-l-(tetrahydro-2H-pyran-2-yl)-6-((tetrahydro-2H-pyran-4-vl3,3,4,5,5-ds)ethynyl)-1H-indazole (C139).

Under N₂ atmosphère, trimethyl((tetrahydro-277-pyran-4-yl-3,3,4,5,5-i7₅)ethynyl)silane C137 (27.6 g, 147.4 mmol) and 5-bromo-6-iodo-l-(tetrahydro-2Æ-pyran-2-yl)-l/7-indazole C138 (50.0 g, 122.8 mmol) were dissolved în water (4.4 mL, 245.7 mmol), 1,4-dioxane (370 mL) and Et₃N (261 g, 358 mL, 2579.5 mmol). Nitrogen was bubbled through the mixture vigorously for 30 min. Cul (93.6 mg, 491.3 pmol), PdCi₂(PPh₃)₂ (344.9 mg, 491.3 pmol) and TBAF (3.8 g, 14.7 mL, 14.7 mmol) were added while degassing. The reaction mixture was degassed with nitrogen gas for and additional 5 min and stirred at room température (brown suspension). After 4 h and 20 min, the reaction mixture was fïltered (yellow solid removed), washed with THF (4x 90 mL) and concentrated. The crude (black viscous oil) was dissolved in MeOH (200 mL) and H₂O (1 L). A viscous black oil precipitated together with a fine émulsion and the mixture was left standing to settle ovemight. The H₂O/MeOH mixture was decanted and the remaining black oil with orange solid was dissolved in CH₂C1₂ (300 mL) and dried over Na₂SO₄. The mixture was fïltered, washed with CH₂C1₂ (4 x 80 mL) and concentrated to give a black oil (58.7 g). Silica gel chromatography (Gradient:0-30 % EtOAc/heptanes), afforded an orange solid (40.8 g) which was dissolved in EtOAc (170 mL) and left stirring at room température ovemight. A white solid was collected by filtration, washed with EtOAc (50 mL), TBME (2x75 mL), and heptanes (2x100 mL), and then dried in vacuo at 50 °C. 30.71 g (63.4 % yield). The mother liquor was concentrated (orange solid 9.9 g), dissolved in EtOAc (50 mL) at reflux and then TBME (50 mL) and heptanes (20 mL) were added. The mixture was stirred at room température over the weekend, fïltered and washed with TBME (4 x 30 mL). Drying in vacuo at 50 °C afforded the product as an off-white solid (6.2 g, 13 % yield).

Total yield: 36.9 g (76 % yield). ^lH NMR (300 MHz, CDC1₃) δ 7.94 (s, IH), 7.93 (s, IH), 7.73 (s, IH), 5.67 (dd, J= 9.2, 2.7 Hz, IH), 4.01 (d, J= 11.7 Hz, 3H), 3.75 (ddd, J= 12.8, 10.0, 3.4 Hz, IH), 3.61 (d, J= 11.6 Hz, 2H), 2.61-2.43 (m, IH), 2.19-2.01 (m, 2H), 1.80-1.63 (m, 3H).

Step 5. Synthesis of 5-(4-Fluoro-3-methylphenyl)-l-(tetrahydro-2H-pyran-2-yl)-6-(tetrahydro2H-pyran-4-yL3,3,4,5,5-d₅)-1,5-dihydropyrrolo[2,3-f]indazole (Cl40)

A mixture of 5-bromo-l-(tetrahydro-2H-pyran-2-yl)-6-((tetrahydro-2Z/-pyran-4-yl3,3,4,5,5-i/5)ethynyl)-17/-indazoIe C139 (42.7 g, 108.3 mmol), zBuXPhos Pd Gl (4.3 g, 5.4 mmol) and zBuXPhos (459.7 mg, 1.1 mmol) were suspended in 1,4-dioxane (110 mL) and zBuOH (330 mL). The reaction mixture was heated to 60 °C and nitrogen gas was bubbled through the solution for 30 min. 4-Fluoroaniline (18.5 g, 15.4 mL, 162.4 mmol) and KOtBu (36.4 g, 324.8 mmol) were added (exotherm from 62 to 80 'C observed; brown suspension) and 410 nitrogen gas was bubbled through the suspension for an additional 10 min. The reaction mixture was stirred at 73-75 °C for -3 h. Water (300 mL), sat. aq. NH₄CI (150 mL) and CH₂Cl₂ (300 mL) were added and the phases separated. The aqueous layer was extracted with CH₂Cl₂ (2x300 mL). The combined organic phases were washed with sat. aq. NH₄Cl (2x100 mL), dried over Na₂SO₄ and concentrated to a brown solid (61.4 g). The crude product was dissolved in CH₂CL (450 mL) and stirred with charcoal (22 g) and SiliaMetS-DMT (8 g) for I h. The mixture was filtered through a Celite® plug and washed with CH₂C1₂ (4x80 mL), giving a clear yellowbrown solution, which was concentrated to a brown solid 43.6 g. The crude product was dissolved in CH₂C1₂ (60 mL) and ZPrOH (350 mL) was added. The CH₂C1₂ was removed under reduced pressure, resulting in heavy précipitation. TBME (100 mL) was added and the suspension stirred ovemight at room température. A yellow solid was collected by filtration, washed with iPrOH (3x50 mL) and dried in vacuo at 50 °C affording the product (26.7 g, 58 % yield). The mother liquor was concentrated to about 120 mL and left stirring ovemight. The solid was filtered and washed with iPrOH (3x40 mL) and TBME (2x40 mL). Drying in vacuo at 50 °C afforded additional product as a beige solid 2.25 g (4.9 % yield). Total yield: 28.95 g (63 % yield). *H NMR (300 MHz, CDC1₃) δ 7.97 (s, IH), 7.67 (s, IH), 7.42-7.22 (m, 4H), 7.19 (s, IH), 6.49 (s, IH), 5.76 (dd, J= 9.3, 2.6 Hz, IH), 4.15-3.91 (m, 3H), 3.85-3.69 (m, IH), 3.34 (d, J= 11.6 Hz, 2H), 2.75-2.51 (m, IH), 2.14 (dd, J=2L8, 10.5 Hz, 2H), 1.93-1.61 (m, 3H).

Step 6. Synthesis of5-(4-Fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl-3,3,4,5,5-d₅)-I,5dihydropyrrolo[2,3-f]indazole-pTsOH (C141)

5-(4-fluorophenyl)-l-(tetrahydro-2Æ-pyran-2-yl)-6-(tetrahydro-27/-pyran-4-yl-3,3,4,5,5î/₅)-1 ,5-dihydropyrroIo[2,3-flindazole C140 (67.9 g, 160 mmol) was suspended in MeOH (600 mL), EtOAc (600 mL) and H₂O (300 mL). TsOHTI₂O (152 g, 800 mmol) was added and the mixture, a yellow suspension, was stirred at 55 ± 5 °C for 1 h (color changes to black-brown). Full conversion was determined by HPLC. The reaction mixture was concentrated to a yellow solid, suspended in H₂O (-1.4 L), stirred for 10 min, filtered, and washed with H₂O (3x200 mL). The wet yellow solid obtained was again suspended in 1.75 L H₂O with 5.5 mL NaOH (10 M) added and stirred for 45 min (pH > 12). The suspension was filtered, washed with H₂O (4x150 mL) and heptanes (2 χ 150 mL), and dried in vacuo at 50 °C for 3.45 h to afford the product as a pale-yellow solid: 77.2 g (97.6 % yield).

‘H NMR (300 MHz, CDC1₃) δ 8.53 (s, IH), 7.95-7.83 (m, 3H), 7.8 - 7.26 (m, 5H), 7.17 (d, J= 8.0 Hz, 2H), 6.53 (s, IH), 3.98 (d, J= 11.7 Hz, 2H), 3.33 (d, J= 11.6 Hz, 2H), 2.34 (s, 3H). Step 7. l-(5-(4-Fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl-3,3,4,5,5-ddpyrrolof2,3-]]indazoL 1 (5H)-yl)-2,2-dimethylpropan-l-one (C142)

411

5-(4-fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl-3,3,4,5,5-d₅)-l-tosyl-l,5dihydropyrrolo[2,3-f]indazole C141 (77.2 g, 156.09 mmol) was suspended in THF (1.60 L) and cooled to 8 °C (ice bath). KOtBu (43.79 g, 390.2 mmol) was added and stirred for 5 min (small exothcrm to 14 °C, brown suspension). At 10 °C, pivaloyl chloride (75.3 g, 76,8 mL, 624.3 mmol) was added drop-wise, and the mixture was stirred at 10-20 °C for 15 min, then warmed to room température for 1.5 h. The reaction was quenched with water, EtOAc, and sat. aq. NaHCO₃. The layers were separated. The organic phase washed with sat. aq. NaHCO₃ (3x100 mL), dried over Na₂SO₄, filtered and concentrated to a yellow-brown solid. The crude was suspended at reflux in EtOH (400 mL) and H₂O (800 mL) was added. The mixture was cooled to room température while stirring, and the solid was filtered, then washed with H₂O (150 mL, yellow fïltrate) and heptanes (200 mL, dark orange fïltrate). The wet product (85 grams) was dissolved in CH₂C1₂ (1 L), washed with brine (100 mL) and dried over Na₂SO₄ to afford the product (58.6 g, 88 %). ‘H NMR (299 MHz, CDC1₃) δ 8.67 (d, J= 1.0 Hz, IH), 8.04 (d, J= 0.9 Hz, IH), 7.45-7.23 (m, 4H), 7.18 (d, J= 1.0 Hz, IH), 6.56 (d, J= 0.9 Hz, IH), 3.98 (d, J= 11.6 FIz, 2H), 3.33 (d, J= 11.6 Hz, 2H), 1.58 (d, J= 1.2 Hz, 9H).

Step 8. l-(5-(4-Fluorophenyl)-7-iodo-6-(tetrahydro-2H-pyran-4-yl-3,3,4,5,5-d_}jpyrrolo[2.3j] indazol-1 (5H)-yl)-2,2-dimethylpropan-1 -one (C143)

A solution of l-(5-(4-fluorophenyl)-6-(tetrahydro-2//-pyran-4-y]-3,3,4,5,5rf₅)pyrrolo[2,3-/|indazol-l(5/7)-yl)-2,2-dimethylpropan-l-one C142 (58.6 g, 138 mmol) in CH₂C1₂ (750 mL) (dark-brown solution) was treated with N-iodosuccinimide (34.2 g, 1.1 eq, 152 mmol) over 40 min (orange suspension). The reaction mixture was stirred at room température for 30 min. The mixture was washed with water (2x150 mL), 10 % aq. Na₂S₂O₅ (200 mL) and brine (100 mL) and dried over Na₂SO₄ and concentrated affording 76 gram of the product. Purification by silica gel chromatography (Eluent: CH₂C1₂, then a gradient of 1-5 % EtOAc in CH₂C1₂) afforded the product as an off-white solid. l-(5-(4-fluorophenyl)-7-iodo-6-(tetrahydro2Æ-pyran-4-yl-3,3,4,5,5-ri₃)pyrrolo[2,3_:/]indazol-l(5E/)-yl)-2,2-dimethylpropan-l-one (66.0 g, 86.9 % yieid) NMR (300 MHz, CDC1₃) δ 8.59 (s, IH), 8.05 (s, IH), 7.38-7.27 (m, 4H), 7.06 (s, IH), 4.01 (d, 11.7 Hz, 2H), 3.34 (d, J= 11.6 Hz, 2H), 1,59 (s, 9H). ^I9F NMR (282 MHz,

CDC1₃) δ-110.96.

Step 9. 4-(5-(4-Fluorophenyl)-l-pivaloyl-6-(tetrahydro-2H-pyran-4-yl-3,3,4,5,5-dy-l,5dihydropyrrolo]2,3-f]indazol-7-yl)benzoate (C144)

A mixture of I-(5-(4-Fluorophenyl)-7-iodo-6-(tetrahydro-2//-pyran-4-yl-3,3,4,5,5Apyrrolo[2,3_:/]indazol-l(5A-yl)-2,2-dimethylpropan-l-one C143 (56.9 g, 0.10 mol) and (4(methoxycarbonyl)phenyl)boronic acid (31g, 1.7 eq, 0,17 mol) were suspended in 1,4dioxane (750 mL) (yellow suspension) and purged with nitrogen for 30 min. 2M aq. Na₂CO₃ 412 ¢0.18 L, 3,6 eq, 0,36 mol) was added and the mixture purged with nitrogen for an additional 5 min. Pd(dppf)CÏ₂ (4.0 g, 0.05 eq, 5.2 mmol) was added and the reaction mixture was stirred for 60 min at 60-65 °C (dark-red suspension). The mixture was concentrated, water (500 mL) was added and the mixture was extracted with CH₂C1₂ (2x200 mL). The combined organic layers were washed with brine (150 mL) and flushed over a plug of silica gel. The product was further eluted from the silica plug with 10 % EtOAc in CH₂C1₂. The product fractions were concentrated to - 1 L. Scavenger resin (25 g, SiliaMetS DMT, 40-63 pm, 60 Â) was added to the mixture and stirred for 1 h. The mixture was then filtered and concentrated. Purification by silica gel chromatography (Gradient: 1-3 % EtOAc in CH₂C1₂) afforded the product as a white solid (49.1 g, 88% yield). Methyl 4-(5-(4-fluorophenyl)-l-pivaloyl-6-(tetrahydro-2H-pyran-4-yl-3,3,4,5,5c/₅)-l,5-dihydropyrrolo[2,3-/]indazol-7-yl)benzoate.

‘H NMR (300 MHz, CDC1₃) δ 8.42 (s, IH), 8.22-8.12 (m, 2H), 8.04 (d, J= 0.7 Hz, 1H),7.56 (d, J= 8.4 Hz, 2H), 7.43 (ddt, J= 8.1, 5.3, 2.7 Hz, 2H), 7.38-7.26 (m, 2H), 7.09 (d, J= 1.0 Hz, IH), 3.99 (s, 3H), 3.83 (d, J= 11.6 Hz, 2H), 3.18 (d, J= 11.6 Hz, 2H), 1.54 (s, 9H).

Step 10.4-(5-(4-Fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl-3,3,4,5,5-d_s)-I,5dihydropyrrolo[2,3-f]indazol-7-yl)benzoic acid (123)

To a solution of methyl 4-(5-(4-fluorophenyl)-l-pivaloyl-6-(tetrahydro-2/7-pyran-4-yl3,3,4,5,5-^)- l,5-dihydropyrrolo[2,3-/]indazol-7-yl)benzoate C144 (21.0 g, 37.6 mmol) was dissolved in THF (200 mL) and MeOH (100 mL) was added 2M aq. NaOH (75.2 mL, 4 eq, 150 mmol). The mixture was heated to 60 °C for 1 h. The organic solvents were evaporated, the residue was diluted with water (350 mL) and washed with EtOAc (2x150 mL). The aqueous solution was acidified with 3N aq. HCl to pH 1 and the precipitate was taken up EtOAc/MeOH (97:3). The organic layer was washed with brine (150 mL), dried over Na₂SO₄ and concentrated. The residue was refiuxed in CH₃CN (200 mL) and stirred for 30 min. The solid was filtered off after cooling to room température, and then dried in vacuo. The material was partially taken up in refluxing IP A (200 mL) and filtered hot. The filtrate was allowed to crystal lize and the crystals were collected by filtration. The product was dissolved in DMSO (60 mL, warm) and slowly added to water (1 L, HPLC-grade). The milky solution was heated to approximately 80 °C until the morphology of the precipitate had changed (10 min). The solid was then collected by filtration, and washed with water (2x100 mL). The product was dried overnight in a circulation oven at 45 °C to afford the product as a white solid. (10.4 g, 60.1% yield). 4-(5-(4fluorophenyl)-6-(tetrahydro-2/f-pyran-4-yl-3_s3,4,5,5-rf₅)-l,5-dihydropynOlo[2,3_:/|indazoL7yl)benzoic acid

413 ‘H NMR (300 MHz, DMSO-c/₆) δ 8.10 (d, J= 8.3 Hz, 2H); 7.98 (s, IH); 7.67-7.58 (m, 4H); 7.58-7.42 (m, 2H); 7.25 (d, 1.1 Hz, IH); 7.06 (d, 1.1 Hz, IH); 3.70 (d, 11.5 Hz,

2H); 3.07 (d, J= 11.5 Hz, 2H).

¹⁹F NMR (282 MHz, DMSO-<7₆) δ -112.57.

Compound 124

4-[6-[2-(difluoromethoxy)-l,l-dimethyl-ethyl]-5~(4-jluorophenyl)-lH-pyrrolo[2,3-f]indazol7-yl] benzoic acid (124)

Step 1. Synthesis of methyl 4-[4-(difluoromethoxy)-3,3-dimethyl-but-I-ynyl]benzoate (CI45)

To a solution of methyl 4-(4-hydroxy-3,3-dimethyl-but-I-ynyl)benzoate C123 (190 mg,

0.82 mmol) and Cul (25.3 mg, 0.13 mmol) in MeCN (2.3 mL) was added 2,2-difluoro-2fluorosulfonyl-acetic acid (68.8 pL, 0.67 mmol). The reaction mixture was allowed to stir for 2 h at 50 °C. Water and CH2CI2 were added, and the organic layer was collected through a phase separator. Purification by reversed-phase chromatography (Column: Cl8. Gradient: 0-100 %

MeCN in water with 0.1 % formic acid) afforded the product (38 mg, 19%). LCMS m/z 283.1 [M+l].

414

Step 2. Synthesis of methyl 4-[6-[2-(difluoromethoxy)-l_ll-dimethyl-ethyl]-1-(2,2dimethylpropanoyl)-5-(4-fluorophenyl)pyrrolo[2,3-f]indazol-7-yl]benzoate (C146)

Compound C146 was prepared from C118 (45 mg, 0.12 mmol) and C145 using the method described for the préparation of C119 in the synthesis of compound 117. Purification by 5 silica gel chromatography (Gradient: 0-100 % EtOAc in heptane) afforded the product (41 mg, 48%). LCMS m/z 592 A [M+l]⁴.

Step 3. Synthesis of 4-[6-[2-(difluoromethoxy)-l,l-dimethyl-ethyl]-5-(4-fluorophenvl)-lHpyrrolo [2,3-f] indazol-7-yl] benzoic acid (124)

Compound 124 was prepared from C146 (41 mg, 0.07 mmol) by hydrolysis with sodium 10 hydroxi de as described for the synthesis of compound 117 from Cl 19. Purification by reversedphase chromatography (Column: Cl8. Gradient: 0-100 % MeCN in water with 0.1 % formic acid) afforded the product (21 mg, 59%). *H NMR (400 MHz, DMSO-îZ₆) δ 13.03 (s, IH), 12.51 (s, IH), 8.07 (d, J = 7.7 Hz, 2H), 7.97 (s, IH), 7.63 - 7.55 (m, 4H), 7.49 (t, J = 8.4 Hz, 2H), 6.85 (s, 2H), 6.58 - 6.55 (m, IH), 3.67 (s, 2H), 1.12 (s, 6H). LCMS m/z 494.1 [M+l]⁴.

Compound 125

4-[6-(2-cyano-l, l-dimethyl-ethyl)-5-(4-fluorophenyl)-lH-pyrrolo[2,3-f] indazol- 7-yl] benzoic acid (125)

415

Step 1. Synthesis of methyl 4-[6-(2-cyano-l,l-dimethyl~ethyl)-l-(2,2-dimethylpropanovl)-5-(4fluorophenyl)pyrrolo[2,3-f]indaΣol-7-yl] benzoate

Compound C148 was prepared from C118 (50 mg, 0.13 mmol) and C147 as described for C146. Silica gel chromatography (Gradient: 0-100 % EtOAc/heptane) afforded the product (42 mg, 44%). LCMS m/z 551.1 [M+l]\

Step 2. Synthesis of 4-[6-(2-cyano-l,l-dimethyl-ethyl)-5-(4fluorophenyl)-lH-pyrrolo[2,3f]indazol-7-yl]benzoic acid (125)

Compound 125 was prepared from C148 by hydrolysis with sodium hydroxide as described for the synthesis of compound 117 from Cl 19. Purification by reversed-phase chromatography (Column: Cl8. Gradient: 0-100 % MeCN in water with 0.1 % formic acid) afforded the product (4.8 mg, 13%). 'H NMR (300 MHz, DMSO-rf₆) δ 13.04 (s, IH), 12.54 (s, IH), 8.10 (d, J = 8.2 Hz, 2H), 7.99 (s, IH), 7.69 - 7.60 (m, 4H), 7.58 - 7.48 (m, 2H), 6.88 (s, 2H), 2.63 (s, 2H), 1.25 (s,6H). LCMS m/z 453.1 [M+l]\

Compound 126

4-[5-(4-fiuorophenyl)-6-methylsulfonyl-lH-pyrrolo[2,3-f]indazol-7-yl]benzoic acid (126)

Step 1. Synthesis of methyl 4-[6-bromo-l-(2,2-dimethylpropanoyl)-5-(4fluorophenyl)pyrrolo[2,3-j]indazol- 7-yl]benzoate (Cl49)

To a solution of methyl 4-[1 -(2,2-dimethylpropanoyl)-5-(4-fluorophenyl)-6trimethylsilyl-pyrroIo[2,3-f]indazol-7-yl]benzoate C93 (76.6 mg, 0.14 mmol) în CH₂C1₂ (3.9 416 mL) was added N-bromosuccinimide (25 mg, 0.14 mmol). The mixture was allowed to stir at room température ovemight. The mixture was diluted wîth dichloromethane and washed with water. The organic phase was passed through a phase separator and concentrated to dryness under reduced pressure to give methyl 4-[6-bromo-l-(2,2-dimethylpropanoyl)-5-(4fluorophenyl)pyrrolo[2,3-f]indazol-7-yl]benzoate (74 mg, 95%). 'H NMR (300 MHz, DMSOd₆) δ 8.62 (t, J = 0.9 Hz, IH), 8.48 (d, J = 0.8 Hz, IH), 8.21 - 8.15 (m, 2H), 7.88 - 7.81 (m, 2H), 7.72 - 7.66 (m, 2H), 7.58 (d, J = 1.0 Hz, IH), 7.57 - 7.49 (m, 2H), 3.91 (s, 3H), 1.49 (s, 9H). LCMS m/z 548.1 [M+l]⁺.

Step 2. Synthesis of methyl 4-[l-(2,2-dimethylpropanoyl)-5-(4-fluorophenyl)-6-methylsulfonylpyrrolo[2,3-f]mdazol- 7-yl]benzoate (Cl 50)

A solution of methyl 4-[6-bromo-1 -(2,2-dimethylpropanoyl )-5-(4fluorophenyl)pyrrolo[2,3-f]indazol-7-yl]benzoate C149 (53 mg, 0.09 mmol), and sodium methanesulfmate (58 mg, 0.57 mmol) in DMSO (1 mL) was heated to 110 C ovemight. Additional sodium methanesulfmate (58 mg, 0.57 mmol) was added and the mixture was heated ovemight at the 110 °C. Water (10 mL) was added, and the mixture washed with Ethyl Acetate. The organic layer was dried over sodium sulfate. The water layer was washed with additional Ethyl Acetate (10 mL) and then over sodium sulfate. The combined organic layers were purified by silica gel chromatography (Gradient: 0-100% ethyl acetate in heptane) to afford the product (15.5 mg, 30%). 'H NMR (300 MHz, Chloroform-d) δ 8.66 - 8.62 (m, IH), 8.27 - 8.21 (m, 2H), 8.16 - 8.13 (m, IH), 7.76 - 7.70 (m, 2H), 7.61 - 7.54 (m, 2H), 7.38 - 7.30 (m, 3H), 4.01 (s, 3H), 2.87 (s, 3H), 1.58 (s, 9H). LCMS m/z 548.2 [M+l]\

Step 3. Synthesis of 4-[5-(4-fhiorophenyl)-6-methylsulfonyl-lH-pyrrolo[2,3-f] indazol-7yl]benzoic acid (126)

Compound Ï26 was prepared from Cl50 (15.5 mg, 0.03 mmol) by hydrolysis with LiOH was în methanol (1 mL) and THF (I mL). Purification by reversed phase chromatography (Cl 8 column. Gradient: 10-100% MeCN in water with 0.1% fonnic acîd modifier) afforded the product (6.6 mg, 47%). 'H NMR (300 MHz, Methanol-J₄) δ 8.21 - 8.15 (m, 2H), 8.09 (d, J = L l Hz, IH), 7.74 - 7.68 (m, 2H), 7.65 - 7.58 (m, 2H), 7.54 (t, J = 1.2 Hz, IH), 7.41 - 7.34 (m, 3H), 2.99 (s, 3H). LCMS m/z 450.1 [M+lf.

417

Compound 127

5-(4~fluorophenyl)-6-(2-methoxy-l,I-dimethyl-ethyl)-7-(6-methylsulfonyl-3-pyridyl)-lHpyrrolo[2,3-f]indazole (127)

To a mixture of l-[5-(4-fluoroph en yl)-7-iodo-6-(2~m ethoxy-l,I-dimethyl-ethyl)pyrrolo[2,3f]indazoI-I-yl]-2,2-dimethyl-propan-l-one S1I (50 mg, 0,09 mmol), (6-methylsulfonyl-3pyridyl)boronic acid (57 mg, 0.28 mmol), and K₃PO₄ (68 mg, 0.32 mmol) in 1,4- dioxane (720 pL) and water (140 pL) were added SPhos Pd G4 (10 mg, 0.013 mmol) was then added, and the reaction was heated to 60 °C overnight. Additional (6-methylsulfonyl-3-pyridyl)boronic acid (50 mg, 0.25 mmol) was added and the mixture degassed with N₂ for 10 min. Additional SPhos Pd G4 (11 mg, 0.02 mmol) was added and the mixture and heated to 80 °C. The mixture was allowed to stir over 3 days. The reaction was diluted with water (5 mL) and dîchloromethane (5 mL), and passed through a phase separator. The organic phase was collected and concentrated in vacuo. This residue was dissolved in THF (1 pL) and MeOH (500 pL), and then NaOH (544 pL of 1 M, 0.54 mmol) was added. The solution was stirred at 50 °C for 1 h. The solvent was evaporated, and the residue was suspended in water, and neutralized with HCl (544 pL of I M, 0.54 mmol). Purification by SFC chromatography afforded the product as a light yellow solid (11.8 mg, 27%). ’H NMR (400 MHz, Méthanol-^) δ 8.84 (s, IH), 8.22 (s, 2H), 7.95 (s, IH), 7.54 (dd, J = 8.5, 4.9 Hz, 2H), 7.39 (t, J = 8.4 Hz, 2H), 6.95 (s, IH), 6.91 (s, IH), 3.35 (s, 3H), 3.16 -3.07 (m, 5H), 1.16 (s, 6H). LCMS m/z 493.1 [M+l]⁺.

418

Compound 128

4-[5-(4-fluorophenylf6-(2-methoxy-l, I-dimethyl-ethyl)-lH-pyrrolo[2,3-j]indazol-7-

Syn thesis of 4-[5-(4fluoroph enyl)-6-(2-methoxy-l, 1 -dimethyl-ethylflH-pyrrolo [2,3-f] indazol- 7yljbenzamide (128)

To a solution of 4-[5-(4-fluorophenyl)-6-(2-methoxy-l,l-dimethyI-ethyl)-lH-pyrrolo[2,3f]indazol-7-yl]benzoic acid 112 (10 mg, 0.02 mmol) and HATU (10 mg, 0.03 mmol) dissolved 10 in DMF (200 pL). DIPEA (14 pL, 0.08 mmol) was added and the reaction was stirred at room temperature for 5 min. Ammonia (5 pL of 30 %w/w, 0.08 mmol) was added and the reaction stirred for 10 min. Purification by reversed-phase HPLC (Method: Cl 8 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H₂O with 0.2 % formic acid) afforded the product as a white solid (8.1 mg, 80%). ^lH NMR (400 MHz, DMSO-î7₆) δ 12.49 (s, IH), 8.07 (s, IH), 15 8.00 (d, J = 8.2 Hz, 2H), 7.96 (s, IH), 7.63 - 7.54 (ni, 2H), 7.55 - 7.40 (m, 5H), 6.83 (d, J = 7.8

Hz, 2H), 3.06 (s, 2H), 3.01 (s, 3H), 1.Π (s, 6H). LCMS m/z 457.2 [M+l]⁺.

419

Compound 129

4-[5-(4-fluorophenyl)-6-(2-methoxy-l,l-dimethyl-ethyl)-3-methyl-IH-pyrrolo[2,3f]indazol-7-yl]benzoic acid (129)

Pd(PPh₃)₂CI₂ Cul

C151

Préparation of l-[5-(4-fluorophenyl)~7-iodo-6-(2-methoxy-l. 1 -dimethyl-ethyl)-3-methylpyrrolo[2,3-f]indazol-l-yl]-2,2-dimethyl-propan-l-one (C156)

Cl56 was prepared in five steps from C151 according to the method described for the préparation of SU. ^JH NMR (400 MHz, DMSOZ₆) δ 8.44 (s, IH), 7.54 - 7.42 (m, 4H), 6.84 (s, IH), 3.56 (s, 2 H), 3.15 (s, 3H), 2.46 (s, 3H), 1.51 (s, 9H), 1.36 (s, 6H). LCMS m/z 562.0 10 [M+l]⁺.

420

Préparation of 4-[5-(4-fiuorophenyl)-6-(2-methoxy-l,l-dimethyl-ethyl)-3-methyl-lHpyrrolo[2,3-f] indazol-7-yl] benzoic acid (129)

Compound 129 was prepared in two steps from compound C156 using the method described for the préparation of compound 127. Reversed phase chromatography (ClS column. Gradient: 10-100% acetonitrile in water with 0.2% formic acid) afforded the product as a white solid (9.1 mg, 45%). ‘H NMR (400 MHz, DMSO-</₆) δ 13.05 (s, IH), 12.05 (s, IH), 8.14 - 8.02 (m, 2H), 7.58 (td, J = 8.8, 7.7, 4.6 Hz, 4H), 7.49 (t, J = 8.1 Hz, 2H), 6.77 (s, IH), 6.70 (s, IH), 3.04 (s, 2H), 3.00 (s, 3H), 2.37 (s, 3H), 1.10(s,6H). LCMS m/z 472.1 [M+I]⁴.

Compound 130

5-(4-fluorophenyl)-6-(2-methoxy-l,l-dimethyl-ethyl)-3-methyl-7-(6-methylsulfonyl-3pyridyl)-] H-pyrrolo[2,3-f]indazole (130)

Step 1. Synthesis of l-(5-(4-fhiorophenyl)-6-(l-methoxy-2-methylpropan-2-yl)-3-methyl-7-(6(methylsulfonyl)pyridin-3-yl)pyrrolo[2,3-f] indazol-1 (5H)-yl)-2,2-dimethylpropan-l-one

A solution of l-[5-(4-fluorophenyl)-7-iodo-6-(2-methoxy-l,l-dimethyl-ethyl)-3-methylpyrrolo[2,3-f]indazol-l-yl]-2,2-dimethyl-propan-l-one C156 (58 mg, 0.10 mmol), (6methylsulfonyl-3-pyridyl)boronic acid (40 mg, 0.20 mmol), and K3PO4 (96 mg, 0.45 mmol) 1,4dioxane (500 pL) and water (100 pL) was purged with N₂ for 10 min. SPhos Pd G4 (9 mg, 0.012 mmol) was added, and the reaction was heated to 80 °C. After 6 hours, the reaction was purged with N₂, and added additional (6-methylsulfonyl-3-pyridyl)boronic acid (37 mg, 0.18 mmol) and SPhos Pd G4 (9 mg, 0.012 mmol) were added. Heating at 80 °C was continued over 3 days. Water (5 mL) and dichloromethane (5 mL) were added, and the mixture was passed through a phase separator. The organic phase was collected, the solvent evaporated and the product used directly in the subséquent step.

421

Step 2, Synthesis of 5-(4-fluorophenyl)-6-(2-methoxy-lJ-dimethyl-ethyl)-3-methyl-7-(6methylsulfonyl-3-pyridyl)-1 H-pyrrolo[2,3-f]indazole (130)

The product from step 1 dissolved in THF (2 mL) and MeOH (1000 pL), and NaOH (605 pL of 1 M, 0.61 mmol) was added. The reaction was heated to 50 °C for 30 min. The solvent 5 was evaporated, and the crude material was suspended in water (2 mL). HCI (605 pL of 1 M, 0.61 mmol) was added to neutralize the mixture. Purification by SFC afforded the product as a light yellow solid. 5-(4-fluoiOphenyl)-6-(2-methoxy-I,l-dimethyl-ethyl)-3-methyl-7-(6methylsulfonyl-3-pyrîdyl)-I H-pyrrolo[2,3-f]indazole (4.3 mg, 8%). LCMS m/z 507.1 [M+l]⁺.

Compound131

4-[5-(5-fluoro-2-pyridyl)-6-(4-hydroxytetrahydropyran-4-yl)-lH-pyrro!o[2,3-f] indazol- 7yl]benzoic acid (131)

Step 1. Synthesis of methyl 4-]2-(4-hydroxytetrahydropyran-4-yl)ethynyl] benzoate (C1S8)

422

C158 was prepared from Cl57 using the method described for the préparation of compound C123 (NEt₃ was substituted for Et₂NH). Purification by silica gel chromatography (Gradient: 0-100 % EtOAc in heptane) afforded the product. (0.92 g, 92%). ‘H NMR (300 MHz, DMSOA) δ 8.01 - 7.89 (m, 2H), 7.63 - 7.51 (m, 2H), 5.83 (s, IH), 3.86 (s, 3H), 3.79 (dt, J = 11.7, 4.6 Hz, 2H), 3.57 (ddd, J = 11.6, 8.6, 3.1 Hz, 2H), 1.94 - 1.89 (m, IH), 1.89 - 1.83 (m, IH), 1.71 (ddd, J = 12.8, 8.6, 3.8 Hz, 2H). LCMS m/z 261.0 [M+l]⁺.

Step 2. 6-chloro-N-(5-fluoro-2-pyridyl)-lH-indazol-5-amine (Cl59)

Compound C159 was prepared from 5-bromo-6-chloro-lH-îndazoIe C95 (0.42 g, 1.80 mmol) and 5-fluoropyridin-2-amîne (230 mg, 2.05 mmol) using the method described for the préparation of C96 in the synthesis of compound 106. Purification by silica gel chromatography (Gradient: 0-100% ethyl acetate in heptane) afforded the product. 6-chloro-N-(5-fluoro-2pyridyl)-lH-indazol-5-amine (327 mg, 68%). ^lH NMR (300 MHz, DMSO-40 δ 13.08 (s, IH), 8.39 (s, IH), 8.08 - 8.03 (m, 2H), 8.01 (d, J = 3.1 Hz, IH), 7.75 - 7.63 (m, IH), 7.50 (ddd, J = 9.2, 8.4, 3.1 Hz, IH), 6.79 (dd, J = 9.2, 3.7 Hz, IH). LCMS m/z 263.0 [M+l]⁺.

Step 3. 1 -[6-chloro-5-[(5-ftuoro-2-pyridyl)amino]indazol-l-yl]-2,2-dimethyl-propan-I-one (C160)

C160 was prepared from Cl59 as described for the synthesis of C97 in the préparation of compound 106. 1 -[6-chloro-5-[(5-lluoro-2-pyridyI)amino]indazol-1 -yl]-2,2-dimethyl-propan-lone (220 mg, 52%). LCMS m/z 347.1 [M+l]⁺.

Steps 4& 5. 4-[5-(5-]hioro-2-pyridyl)-6-(4-hydroxytetrahydropyran-4-yl)-lH-pyrrolo[2,3f] indazol-7-yl] benzoic acid (131)

Compound 131 was prepared in two steps from compound Cl60 using the method described for the préparation of 117. Purification by silica gel chromatography (Gradient: 0-10% methanol in dichloromethane) afforded the product. 4-[5-(5-fluoro-2-pyridyl)-6-(4hydroxytetrahydropyran-4-yl)-lH-pyrrolo [2,3-f] indazol-7-yl] benzoic acid (8.3 mg, 58%). 'H NMR (300 MHz, DMSO-4) δ 13.1 (bs, IH), 12.56 (s, IH), 8.63 (d, J = 3.1 Hz, IH), 8.13 - 8.07 (m, 2H), 8.03 (td, J = 8.5, 3.1 Hz, IH), 7.99 (d, J = 1.0 Hz, IH), 7.70 (dd, J = 8.7, 4.1 Hz, IH), 7.63 - 7.55 (m, 2H), 7.09 (d, J = 1.1 Hz, IH), 6.97 (t, J = 1.1 Hz, IH), 5.10 (s, IH), 3.48 (d, J = 12.6 Hz, 4H), 1.90 (td, J = 12.2, 11.2, 5.3 Hz, 2H), 1.77 (d, J = 13.3 Hz, 2H). LCMS m/z 473.2 [M+l]’.

423

Compound 132

2,6-difluoro-4-[5-(4-fluorophenyl)-3-methyl-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3-f] indazol- 7yl]phenol (132)

C151 C162

Préparation of 1 -[5-(4-fluorophenyl)-7-iodo-3-methyl-6-tetrahydropyran-4-yl-pyrrolo[2,3]]indazol-1-yl]-2,2-dimethyl-propan-l-one (Cl66)

Intermedîate Cl66 was prepared from C151 according to the method described for the préparation of SU. ^lH NMR (400 MHz, DMSO-J₆) δ 8.37 (s, IH), 7.62 - 7.56 (m, 2H), 7.55 7.49 (m, 2H), 7.1 S (s, IH), 3.90 (dd, J = 11.6, 4.1 Hz, 2H), 3.22 (t, J = 11.7 Hz, 2H), 2.98 - 2.85 10 (m, IH), 2.55 - 2.51 (m, 3H), 2.30 (tt, J = 13.8, 6.9 Hz, 2H), 1.70 - 1.60 (m, 2H), 1.51 (s, 9H).

LCMS m/z 559.96 [M+10.

424

Synthesis of 2,6-difluoro-4-[5-(4-fluorophenyl)-3-methyl-6-tetrahydropyran-4-yl-lHpyrrolo[2,3-fjindazol- 7-yl]phénol (132)

Compound 132 was prepared from C166 in two steps using the method described for the préparation of compound 129. Reversed phase HPLC afforded the product as an off-white solid.

2,6-difluoro-4-[5-(4-fluorophenyl)-3-methyl-6-tetrahydropyran-4-yMH-pynOlo[2,3-f]indazol-7yl]phenol (6.1 mg, 13%). LCMS m/z 478.1 [M+lf.

Compounds 133-136

Compounds 133-136 (see Table 10) were prepared in two steps from intermediate C172 and the appropriate boronîc acid or ester via a Suzuki coupling then hydrolysîs, according to the method described for the préparation of compounds 129 and 130. SPhos Pd G4 was used as catalyst and K3PO4 was used as base in the Suzuki coupling step. Sodium hydroxide was used in the final deprotectîon or deprotection/ ester hydrolysîs step.

Table 10. Method ofpréparation, structure, physicochemical data for compounds 133-136

Compound	Method/Product	Boronîc acid or ester	‘H NMR; LCMS m/z [M+H]+
7 2 3	Compound 132from Cl72' 0 Jo nX M H /	O~S il	LCMS m/z 505.1
1J J	aJ Xp ΑΜΑ λ—7 p F	L H B HO OH	[M+l]+

425

Compound	Method/Product	Boronic acid or ester	’H NMR; LCMS m/z [M+H]'
134	Compound 132 from C1721 0 / °'S-NH O H / /--\ N T| [ 7—( 0 0 F	o°s'NHMe 0 HO OH	‘H NMR (400 MHz, DMSO-rf6)Ô 12.14 (s, IH), 7.93 (d, J = 7.9 Hz, 2H), 7.74 (d, J = 7.9 Hz, 2H), 7.63 (dd, J = 8.7, 5.0 Hz, 2H), 7.53 (q, J = 8.6, 6.6 Hz, 3H), 7.18 (s, IH), 6.96 (s, IH), 3.73 (d, J= 10.5 Hz, 2H), 3.17-3.06 (m, 2H), 3.04-2.94 (m, IH), 2.56-2.51 (m, 3H), 2.41 (s, 3H), 1.73 - 1.56 (m, 4H). LCMS m/z 519.1 [M+1]0
135	Compound 132from C172x F-OH ncF-F H / /—\ < J T Fa ? 0 F	O^OMe II R.	LCMS m/z 495,1 [M+l]+
136	Compound 132 from C1721 F-OH O H / n.Ύ TfJ p 0 F	O^OEt 0 A HO OH	’H NMR (400 MHz, M éthanol-^) δ 8.17 (d, J = 7.8 Hz, 2H), 7.61 (d, J = 7.8 Hz, 2H), 7.53 (dd, J = 8.3, 4.9 Hz, 2H), 7.41 (t, J = 8.3 Hz, 2H), 7.24 (s, IH), 7.00 (s, IH), 3.81 (dd, J = 11.4, 3.9 Hz, 2H), 3.22 (t, J = 11.7 Hz, 2H), 3.11 - 3.00 (m, IH), 2.47 (s, 3H), 1.82 (tt, J = 12.5, 6.6 Hz, 2H), 1.72 1.64 (m, 2H). LCMS m/z 470.1 [M+lf

^T Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 15Ü mm, 5 micron). Gradient: MeCN in H₂O with 0.2 % formic acid.

426

Purification by reversed-phase chromatography (Column: Cl8. Gradient: 10-100 % MeCN in water with 0.1 % formic acid) afforded the product.

Compound137

5-(4-fluorophenyl) - 7-(5-methylsulfonyl-2-pyridyl)-6-tetrahydropyran-4-yl-lH-pyrrolo [2,3fl indazole (137)

1. K₃PO₄

SPhos Pd G4

F

C60

Synthesis oj 5-(4-fluorophenyl)-7-(5-methylsulfonyl-2-pyridyl)-6-tetrahydropyran-4-yl-lHpyrrolo[2,3 -f] indazole

Compound 137 was synthesized in two steps from C60 (50 mg, 0.07 mmol), according to the method described for compound 129. Purification by reversed-phase HPLC.Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient; MeCN in H₂O with 0.1 % trifluoroacetic acid (5.7 mg, 14%). ’H NMR (400 MHz, DMSO-<4) δ 12.74 (s, IH), 9.21 (d, J = 2.5 Hz, IH), 8.43 (dd, J = 8.4, 2.5 Hz, IH), 8.04 (s, IH), 7.99 (d, J = 8.4 Hz, IH), 7.75 (s, IH), 7.65 (dd, J = 8.7, 5.0 Hz, 2H), 7.54 (t, J = 8.7 Hz, 2H), 7.08 (s, IH), 3.81 - 3.76 (m, 2H, overlap with water), 3.44 (s, 3H), 3.34 (t, J = 12.2 Hz, IH), 3.19 (t, J = 11.5 Hz, 2H), 1.99- 1.80 (m, 2H), 1.69 (d, J =12.5 Hz, 2H). LCMS m/z 491.1 [M+l]⁺.

Compound 138-143

Compounds 138-143 (see Table 11 ) were prepared in two steps from S4 and the appropriate boronic acid or ester via a Suzuki coupling then hydrolysis, according to the method described for the préparation of compounds 131 and 132. Any modifications to the methods are noted in the footnotes.

427

Table 11. Method ofpréparation, structure, physicochemical data for compounds 138-143

Compound	Meth od/Product	Boronic acid or ester	’H NMR; LCMS m/z [M+H]+
138	Compound 132 from S4X 0 °'S-NH2 O H / NvVi AA A II I /a P ô F	W O --Q I II /A y ζ-ωΑ. n V Z/ ' o x/ 0 z	LCMS m/z 491.1 [M+lf.
139	Compound 132 from S4‘~ N^\ VJ H / NvaA /—\ J 1 H P 0 F	1 o~s=o ό ηο'όη	Ή NMR (400 MHz, DMSO-c/6) δ 12.58 (d, J = 1.4 Hz, IH), 8.27 (dd, J = 2.4, 0.7 Hz, IH), 8.00 (t, J = 1.2 Hz, IH), 7.83 (dd, J = 8.4, 2.4 Hz, IH), 7.65 - 7.56 (m, 2H), 7.55 - 7.46 (m, 2H), 7.14 (t, J = 1.1 Hz, IH), 7.09 (t, J = 0.8 Hz, IH), 7.02 (dd, J = 8.4, 0.8 Hz, IH), 3.96 (s, 3H), 3.73 (d, J = 10.4 Hz, 2H), 3.09 (td, J = 11.2, 3.8 Hz, 2H), 2.90 (m, IH), 1.73 - 1.56 (m, 4H). LCMS m/z 443.2 [M+lf.
140	Compound 132 from S43 S=O N AJ H M X Va p F	oXo AN L if A J)	lH NMR (400 MHz. DMSO-î/6) δ 12.57 (s, IH), 8.17 - 8.08 (m, IH), 8.07 - 7.99 (m, 2H), 7.71 - 7.61 (m, 2H), 7.58 - 7.48 (m, 2H), 7.19 (s, IH), 6.90 (s, IH), 3.82 - 3.60 (m, 2H), 3.41 (s, 3H), 3.07 (q, J = 10.8 Hz, 2H), 2.84 (t, J = 12.4 Hz, IH), 2.44 (s, 3H), 1.80 1.27 (m, 4H). LCMS m/z 505.1 [M+l]+.

428

Compound	Meth od/Product	Boronic acid or ester	’H NMR; LCMS m/z [M+Hf
141	Compound 132 from S4 / F M / O+° H / χ Ύ Ty p R F	I 1 J O^X^O HOBOH	*H NMR (400 MHz, DMSOA) δ 12.57 (s, IH), 7.99 (s, IH), 7.63 7.47 (m, 4H), 7.31 (s, IH), 7.06 (s, IH), 6.90 6.83 (m, 2H), 3.87 (d, J = 1.6 Hz, 6H), 3.75 (d, J = 11.2 Hz, 2H), 3.19 3.07 (m, 2H), 3.06 2.96 (m, IH), 1.75 1.64 (m, 4H). LCMS m/z 490.1 [M+l]+.
142	Compound 132 from S4 —0^^ ΙΓΑ H / NV%X /—\ χ ii i yx p F	1 1 B HO OH	Ή NMR (400 MHz, DMSOA) δ 12.55 (s, IH), 7.99 (s, IH), 7.60 (dd, J = 8.3, 5.0 Hz, 2H), 7.53 - 7.47 (m, 2H), 7.28 (s, 1 H), 7.05 (s, IH), 6.63 (s, 2H), 6.59 (s, IH), 3.82 (s, 6H), 3.78 - 3.71 (m, 2H), 3.10 (t, J = 11.4 Hz, 2H), 3.04-2.95 (m, 1 H), 1.80- 1.60 (m, 4H). LCMS m/z 472.1 [M+l]+.
143	from S4 - See footnotes1,4 O hr nX H / X J! X XX P F	0γ 0 A HO OH	'H NMR (400 MHz, DMSO-î/6) Ô 12.57 (s, IH), 8.23 (d, J =2.4 Hz, IH), 7.99 (s, IH), 7.68 (dd, J = 8.6, 2.5 Hz, IH), 7.59 (dd, J = 8.7, 5.1 Hz, 2H), 7.50 (t, J = 8.7 Hz, 2H), 7.16 (s, 1 H), 7.08 (s, IH), 7.03 (d, J = 8.7 Hz, 1 H), 3.74 (d, J = 11.1 Hz, 2H), 3.62 (m, 8H), 3.09 (m, 2H), 2.88(tm, IH), 2.08 (s,3H), 1.68 (m,4H). LCMS m/z 539.1 [M+lf.

^r Purification by reversed-phase HPLC. Method: Cl 8 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H₂O with 0.2 % formic acid.

429

The methoxy substituted by-product 139 5-(4-fluorophenyl)-7-(6-methoxy-3-pyndyl)-6tetrahydropyran-4-yl-lH-pyrrolo[2,3-f]mdazole was isolated from the two step Suzuki coupling/ pivaloyl group deprotection in addition to compound 138.

³‘ Purification by reversed-phase chromatography (Column: Cl 8. Gradient: 10-100 %

MeCN in water with 0.1 % formic acid) afforded the product.

⁴‘ The Suzuki coupling step was carrîed out using Pd(PPh₃)₄ and Na₂CO₃ in DMF and 1,4dioxane at 150 °C.

Compound 144

4-[l-(4-fluorophenyl)-2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-f]indol-3-yl]benzoic acid

Step 1. Synthesis of l-(benzenesulfonyl)-6-chloro-N-(4-fluorophenyl)indol-5-amine (C169)

To a solution of 6-chloro-N-(4-fluorophenyl)-lH-indol-5~amine C168 (448 mg, 1.68 mmol) in THF (12 mL) at -0 °C (ice-water bath) was added KOtBu (1.9 mL of 1 M, 1.9 mmol).

430

After-ΙΟ min, benzenesulfonyi chloride (287 pL, 2.25 mmol) was added and the reaction stirred for 60 min in an ice bath. The reaction was quenched with water (10 mL), and stirred for 5 min. 50% saturated brine (40 mL) was added and the mixture extracted with EtOAc (100 mL). The organic layer was dried with sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (0-100% ethyl acetate in heptane) afforded the product (305 mg, 43%). ^lH NMR (300 MHz, DMSO-<4) δ 8.03 - 7.92 (m, 3H), 7.78 (d, J = 3.6 Hz, IH), 7.76 - 7.68 (m, IH), 7.66 - 7.59 (m, 2H), 7.57 (s, IH), 7.34 (s, 1 H), 7.11 - 6.98 (m, 4H), 6.75 (dd, J = 3.7, 0.9 Hz, IH). LCMS m/z 401.1 [M+lf,

Step 2. methyl 4-[5-(benzenesulfonyl)-l-(4-fluorophenyl)-2-(4-hydroxytetrahydropyran-4yl)pyrrolo[2,3-f] indol-3-yl] benzoate (Cl 70)

Compound CI69 was prepared from CI70 1 -(benzenesulfonyi)-6-chloro-N-(4fluorophenyl)indol-5-amine (99.5 mg, 0.24 mmol) and Cl 75 methyl 4-(2-(4hydroxytetrahydropyran-4-yl)ethynyl] benzoate (112 mg, 0.43 mmol) using the method described for the préparation of compound C156. Purification by silica gel chromatography (0-100% ethyl acetate in heptane) afforded the product (121 mg, 80%). 'H NMR (300 MHz, DMSOZ₆) δ 8.21 - 8.15 (m, 2H), 7.72 - 7.46 (m, 1 IH), 7.37 (t, J = 8.7 Hz, 2H), 6.82 - 6.74 (m, 2H), 5.12 (s, IH), 3.94 (s, 3H), 3.52 - 3.35 (m, 4H), 1.81 (td, J = 12.9, 5.3 Hz, 2H), 1.55 (d, J = 13.0 Hz, 2H). LCMS m/z 624,1 [M+l]⁺.

Step 3. Synthesis of methyl 4-[5-(benzenesulfonyl)-l-(4-fluorophenyl)-2-tetrahydropyran-4-ylpyrrolo[2,3-Q indol-3-yl]benzoate (Cl 71 )

To a solution of methyl 4-[5-(benzenesulfonyl)-l-(4-fluorophenyl)-2-(4hydroxytetrahydropyran-4-yl)pyrrolo[2,3-f]indol-3-yl]benzoate Cl70 (95 mg, 0.15 mmol) in MeCN (2 mL) at room température was added iodo(trimethyl)silane (100 pL, 0.70 mmol). The reaction was heated at 50 °C for 10 min. The reaction was quenched with water and extracted by CH₂C1₂. The combined organic layer was dried over MgSO₄, filtered and concentrated. Purification by silica gel chromatography (0 to 100% ethyl acetate in heptane) afforded the product cartridge (41 mg, 44%). ‘H NMR (300 MHz, DMSO-<7₆) δ 8.24 - 8.18 (m, 2H), 7.81 7.75 (m, 3H), 7.70 - 7.53 (m, 8H), 7.48 (t, J = 8.7 Hz, 2H), 6.94 (d, J = 0.8 Hz, IH), 6.82 (d, J = 3.9 Hz, IH), 3.94 (s, 3H), 3.71 (d, J = 1 LO Hz, 2H), 3.14 - 3.03 (m, 2H), 3.02 - 2.91 (m, IH), 1.69- 1.55 (m,4H). LCMS m/z 609.1 [M+l]+.

Step 5. Synthesis of 4-[l-(4-fluorophenyl)-2-tetrahydropyran-4-yl-5H-pyrrolo[2,3-f]indol-3yl]benzoic acid (144)

Compound 144 was prepared from compound methyl 4-[5-(benzenesulfonyl)-l-(4fluorophenyI)-2-tetrahydropyran-4-yl-pyrrolo[2,3-f]indol-3-yl]benzoate Cl71 (40 mg, 0.063 mmol) by hydrolysis with NaOH at 80 °C as described in the préparation of compound 129. 431

Purification by reversed-phase HPLC (Method: Cl8 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H₂O with 0.2 % formic acid) afforded the product (l 0.8 ni g, 37%). ’H NMR (300 MHz, DMSO-d₆) Ô 13.01 (s, IH), 10.63 (s, IH), 8.13 - 8.04 (m, 2H), 7.65 - 7.54 (m, 4H), 7.49 (t, J = 8.7 Hz, 2H), 7.29 (t, J = 2.8 Hz, IH), 7.26 - 7.19 (m, IH), 6.85 (s, IH), 6.35 - 6.28 (m, IH), 3.73 (d, J = 11.3 Hz, 2H), 3.17 - 2.93 (m, 3H), 1.71 - 1.60 (m, 4H). LCMS m/z 455.1 [M+l]⁺.

Compound 145

4-[5-(4fhtorophenyl)-6-tetrahydropyran-4-yl-IH-pyrrolo]2,3-f] indazol- 7-yl] benzamîde (145)

Préparation of 4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3-f]indazol-7yl] benzamide (145)

To a solution of 4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrTolo[2,3-f]indazol-7yl]benzoic acid (10 mg, 0.02 mmol) and HATU (10 mg, 0.03 mmol) in DMF (250 pL) was added DIPEA (12 pL, 0.07 mmol) was added, and the reaction was stirred at room température for 5 mîn. Ammonia (10 pL of 30 %w/w) was added and the reaction was stirred at room température for 5 min. The reaction was worked up by addition of water and dichloromethane. The mixture was extracted with dichloromethane (x 3). The organic phases were filtered through a phase separator, combined and the volatiles were evaporated in vacuo. Purification by reversed-phase HPLC (Method: Cl8 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H₂O with 0.2 % formic acid) afforded the product as a white solid (8.4 mg, 82%). 'H NMR (400 MHz, DMSO-^₆) δ 12.59 (s, IH), 8.08 (s, IH), 8.04 (d, J = 8.3 Hz, 2H), 8.00 (t, J = 1.3 Hz, IH), 7.62 (m, 2H), 7.60 - 7.57 (m, 2H), 7.51 (m, 2H), 7.44 (s, IH), 7.23 (t, J = 1.1 Hz, IH), 7.07 (s, IH), 3.73 (d, J = 11.3 Hz, 2H), 3.16 - 3.05 (m, 2H), 2.99 (m, IH), 1.67 (m, 4H). LCMS m/z 455.2 [M+l]⁺.

432

Compound 146

N-(2-(cyclopropylsulfonyl)ethyl)-4-(5-(4-fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-l,5dihydropyrrolo[2,3-fjindazol-7-yî)benzamide (146)

Compound 146 was prepared from compound 33 and 2-(cyclopropylsulfonyl)ethan-l-amine using an amide coupling reaction with HATU as described for compound 145. N-(2cyclopropylsulfonylethyl)-4-[5-(4-fluorophenyI)-6-tetrahydropyran-4-yl-IH-pyrrolo[2,3f]indazol-7-yl]benzamide (24.7 mg, 35%). ’H NMR (400 MHz, Chioroform-d) δ 8.03 (s, IH), 7.93 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.51 - 7.37 (m, 2H), 7.37 - 7.20 (m, 4H), 7.16 7.06 (m, 1 H), 4.19 - 4.04 (m, 2H), 3.83 (dd, J = 11.5, 4.1 Hz, 2H), 3.47-3.38 (m, 2H), 3.20 (td, J = 11.9, 1.9 Hz, 2H), 3.00 (ddt, J = 15.0, 9.2,4.8 Hz, 1 H), 2.51 (tt, J = 7.9, 4.8 Hz, IH), 1.80 (qd, J = 12.5, 4.2 Hz, 2H), 1.63 (s, 2H), 1.32 (qd, J = 5.8, 1.3 Hz, 2H), 1.26 (t, J = 7.1 Hz, IH), 1.13 (tt, J = 7.0, 3.0 Hz, 2H). ¹⁹F NMR (376 MHz, Chloroform-d) δ -111.64. LCMS m/z 587.2 [M+H]⁺.

Compound 147

N-(2-acetamidoethyl)-4-(5-(4~fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-l ,5dihydropyrrolo[2,3-fjindazol-7-yl)benzamide (147)

Compound 147 was prepared from compound 33 and N-(2-aminoethyl)acetamide using an amide coupling reaction with HATU as described for compound 145. N-(2-acetamidoethyl)-4

433

[5-(4-fluorophenyl)-6-tetrahydropyran-4-yI-i H-pynOlo[2,3-f]indazol-7-yl]benzamide (12.9 mg, 21%). 'H NMR (400 MHz, DMSOA) δ 12.60 (s, IH), 8.64 (d, J = 6.2 Hz, IH), 8.01 (d, J = 7.8 Hz, 4H), 7.73 - 7.41 (m, 6H), 7.22 (s, IH), 7.08 (s, IH), 3.73 (d, J = 11.2 Hz, 2H), 3.35 (m, 3H) 3.13 (d, J = 30.7 Hz, 3H), 2.98 (s, IH), 1.84 (s, 3H), 1.67 (s, 4H). ^I9F NMR (376 MHz, Chloroform-rf) δ -112.6 LCMS m/z 540.2 [Μ+Ή]⁺.

Compound148

4.[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3-f] indazol- 7-yl]-N-[2-(2oxooxazolidin-3-yl)ethyl]benzamide (148)

Compound 148 was prepared from compound 33 and 3-(2-aminoethyl)oxazolidin-2-one using an amide coupling reaction with HATU as described for compound 145. 4-[5-(4fluorophenyl)-6-tetrahydropyran-4-yI-lH-pyrrolo[2,3-f]indazol-7-yl]-N-[2-(2-oxooxazolidin-3yl)ethyl]benzamide (5.9 mg, 8%). ‘H NMR (400 MHz, DMSOA) δ 12.58 (s, IH), 8.71 (s, IH), 8.05 - 7.92 (m, 3H), 7.65 - 7.47 (m, 6H), 7.23 (s, IH), 7.07 (s, IH), 4.27 (s, 2H), 3.71 (dd, J = 19.9, 9.6 Hz, 3H), 3.55 - 3.46 (m, 2H), 3.36 (d, J = 20.5 Hz, 3H), 3.10 (s, 2H), 3.00 (s, IH), 1.67 (s, 4H). LCMS m/z 568.2 [M+l]⁺.

Compound 149

4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3-f] indazol- 7-yl]-N- (3methylsulfonylcyclobutyl)benzamide (149)

434

Compound 149 was prepared from compound 33 and 3-methylsulfonylcyclobutanainine hydrochloride sait by an amide coupling reaction with HATU as described for compound 145. 4[5-(4-fluorophenyI)-6-tetrahydropyran-4-yl-lH-pynOlo[2,3-fjindazol-7-yl]-N-(3methylsulfonylcyclobutyl)benzamide (3.1 mg, 3%). ^fH NMR (400 MHz, DMSO-c/₆) δ 12.61 (s, 5 IH), 8.97 (d, J = 7.5 Hz, IH), 8.13 - 7.92 (m, 3H), 7.56 (dt, J = 40.4, 8.5 Hz, 7H), 7.23 (s, IH), 7.08 (s, IH), 4.57-4.40 (m, IH), 3.76 (m, 4H), 3.34 (s, IH), 3.09 (s, 3H), 2.92 (m, 4H), 1.65 (m, 4H). LCMS m/z 587.1 [M+l]⁴.

Compounds 150-159 ¹⁰ Compounds 150-159 (see Table 12) were prepared from S4 using the method described for the préparation of compound 132. SPhos Pd G4 or Pd(PPh₃)₄ was used as the catalyst in the Suzuki reaction step. Any modifications to these conditions are noted in the table and accompanying footnotes.

Table 12. Method ofpréparation, structure, physicochemical data for compounds 148-156

Compound	Method/Product	Boronic acid or ester	'H NMR; LCMS m/z [M+H]4
150	Compound 132 from S4' ^p-OMe /^OMe O H / N-^M-Fx /—\ ΤΥλ p N \---/ f F	CK _OMe 1 OMe f	'HNMR (400 MHz, Methanol-t/4) 5 8.28 (s, IH), 8.02 - 7.85 (m, 3H), 7.72 (ddt, J = 7.8,4.1, Ll Hz, 2H), 7.58 - 7.46 (m, 2H), 7.47 - 7.35 (m, 2H), 7.30 (t, J = 1.1 Hz, IH), 7.12 (d, J = 1.2 Hz, IH), 3.86 (d, J = 11.1 Hz, 8H),3.22(td, 1 = 11.8,2.1 Hz, 2H), 3.15-2.99 (m, IH), 1.81 (qd, J = 12.4,4.3 Hz, 2H), 1.69 (d, J = 13.0 Hz, 2H). LCMS m/z 520.0 [M+l]4.

435

Compound	Method/Product	Boronic acid or ester	'H NMR; LCMS m/z [M+H]+
151	Compound 132 from S4[ θ'ρ-ΟΜε Α0Η O H / a J L / \ p 0 F	Ος. .OMe 1 OMe Φ A 0 0	*H NMR (400 MHz, Methanol-i/4) δ 8.05 7.89 (m,3H), 7.737.61 (m, 2H), 7.58 7.47 (m, 2H), 7.46 7.36 (m, 2H), 7.29 (t, J = 1.1 Hz, IH), 7.13 (d, J = 1.1 Hz, IH), 3.87 3.71 (m, 5H), 3.29 3.12 (m, 2H), 3.12 2.95 (m, IH), 1.82 (qd, J = 12.5,4.3 Hz, 2H), 1.69 (d, J = 12.9 Hz, 2H). LCMS m/z 506.0 [M+l]4
152	Compound 132 from S4~ OMe MeO J XX OMe H / nakA /—\ A J [ Va p A.V^N X-7 0 F	OMe XJ ho'boh	*H NMR (400 MHz, DMSO-4) δ 12.53 (s, IH), 7.99 (d, J = LÜ Hz, IH), 7.58 (ddt, J = 8.4, 5.6, 2.8 Hz, 2H), 7.55 - 7.47 (m, 2H), 7.32 (t, J= ] .1 Hz, IH), 7.04 (d, J = 1.1 Hz, 1 H), 6.77 (s,2H), 3.82 (s, 6H), 3.78 (s, 3H), 3.77 - 3.69 (m, 2H), 3.18-2.97 (m, 3H), 1.80- 1.64 (m, 4H). LCMS m/z 502.1 [M+l]+.
153	From S4 - See footnote3 aV H \=A na\ J Nd TW~a »v F	03 O-B +	’H NMR (400 MHz, DMSO-A) δ 12.61 (s, IH), 8.84 - 8.60 (m, IH), 8.08 (s, IH), 8.01 (s, IH), 7.75 (d, J = 9.2 Hz, IH), 7.70 (s, IH), 7.63 (dd, J = 8.7, 5.0 Hz, 2H), 7.52 (t, J = 8.6 Hz, 2H), 7.38 (d, J = 9.3 Hz, IH), 7.25 (s, IH), 7.12 (s, IH), 3.73 (d, J = 11.2 Hz, 2H), 3.20 - 3.04 (m, 2H), 2.98 (m, IH), 1.70 (ιη, 4H). LCMS m/z 452.2 [M+lf.

436

Compound	Method/Product	Boronic acid or ester	JH NMR; £0/5 m/z [M+H]
154	Compound 132 from S4~ o H / n . J I XX p 0 F	F MeO^^ hoboh	lH NMR (400 MHz, DMSO-î/ô) δ 12.56 (s, IH), 7.99 (s, IH), 7.63 -7.57 (m,2H), 7.50 (t, J = 8.5 Hz, 2H), 7.37 7.29 (m, 2H), 7.26 (d, J = 8.4 Hz, IH), 7.18 (s, IH), 7.Û7 (s, IH), 3.95 (s, 3H), 3.74 (d, J = 11.4 Hz, 2H), 3.17 3.04 (m, 2H), 2.982.88 (m, IH), 1.72 1.61 (m,4H). LCMS m/z 460.1 [M+lf.
155	From S4 - See footnote3 Cj XX H / /---y X 11 J VX p X--/ P F	0 N ô hoboh	lH NMR (400 MHz, DMSO-d6) δ 12.57 (s, IH), 8.23 (d, J = 2.4 Hz, IH), 7.99 (s, IH), 7.68 (dd, J = 8.7, 2.4 Hz, IH), 7.65 - 7.56 (m, 2H), 7.50 (t, J = 8.7 Hz, 2H), 7.16 (s, IH), 7.08 (s, IH), 7.01 (d, J = 8.7 Hz, IH), 3.83 - 3.67 (m, 6H), 3.55 (m, 4H), 3.10 (m, 2H), 2.89 (m, IH), 1.68 (m, 4H). LCMS m/z 498.1 [M+1] K.

437

Compound	Meth od/Product	Boronic acid or ester	‘H NMR; LCMS m/z [M+H]+
156	From S4 - See footnote' 6 nF // y H < II Γ FF o N '---/ F	j~c Pz—C y—co p=/ ________	lH NMR (400 MHz, DMSO-dô) δ 12.57 (s, IH), 8.22 (d, J = 2.4 Hz, IH), 7.99 (s, IH), 7.66 (dd, J = 8.7, 2.5 Hz, IH), 7.59 (dd, J = 8.7, 5.0 Hz, 2H), 7.50 (t, J = 8.7 Hz, 2H), 7.15 (s, IH), 7.08 (s, IH), 7.02 (d, J = 8.8 Hz, IH), 3.74 (d, J = 10.9 Hz, 2H), 3.61 (m, 4H), 3.10 (m, 2H), 2.90 (m, IH), 2.642.56 (m, 4H), 2.34 (s, 3H), 1.68 (m, 4H).LCMS m/z 511.2 [M+l]'.
157	From S4 - See footnoteî OH nF VJ H ! n /—\ < Jl λ FX p F	OH Ô A 0 O H	Ή NMR (400 MHz, DMSO-<) δ 12.61 (s, IH), 11.80 (s, IH), 7.99 (s, IH), 7.63 7.45 (m, 5H), 7.42 (s, IH), 7.22 (s, IH), 7.08 (s, IH), 6.51 (d, J = 9.3 Hz, IH), 3.77 (d, J = 11.3 Hz, 2H), 3.21 3.05 (m, 2H), 2.88 (m, IH), 1.69 (m, 4H). LCMS m/z 429.2 [M+l]'.

438

Compound	Method/Product	Boronic acid or ester	*H NMR; LCMS m/z [M+H]
158	From S4 - See footnote3 Γ<5 O-\j ίΛ H / N /--\ N II Γ >—( 0 N -/ F	/—12 z=/ b y-	ίΗ NMR (400 MHz, DMSO4) δ 12,58 (s, IH), 8.25 (d, J = 2.4 Hz, IH), 8.00 (s, IH), 7.82 (dd, J = 8.4, 2.5 Hz, IH), 7.60 (dd, J = 8.7, 5.0 Hz, 2H), 7.51 (t, J = 8.6 Hz, 2H), 7.16 (s, IH), 7.09 (s, IH), 6.99 (d, J = 8.4 Hz, IH), 5.30 (m, IH), 3.92 (m, 21-1),3.73 (d, J = 11.2 Hz, 2H), 3.58 -3.49 (m, 2H), 3.183.04 (m, 2H), 2.98 2.85 (m, IH), 2.10 (m, 2H), 1.79- 1.55 (m, 6H). LCMS m/z 513.2 [M+l]\
159	From S4 - See footnote3,4 (jA H / n . ] T p Q F	o \ Ln C0'U b y-	Ή NMR (400 MHz, Méthane)!-/^) δ 8.13 7.92 (m, 2H), 7.82 (s, IH), 7.49 (m, 2H), 7.44 - 7.33 (m, 3H), 7.13 (d, J = 1.2 Hz, IH), 5.72 (s, 2H), 3.84 (dd, J = 11.5, 4.3 Hz, 2H), 3.25 (m, 2H), 3.05 (s, 4H), 1.981.84 (m, 2H), 1.68 (d, J =13.2 Hz, 2H). LCMS m/z 494.2 [M+l]+.

439

Compound	Meth od/Product	Boronîc acid or ester	'H NMR; LCMS m/z [M+Hf
160	From S4 - See footnote3'4 00 A— H / /—\ n . J L X p F	0 II o=s— N-N V A 0 0	NMR (400 MHz, Methanol-Jf δ 8.04 (d, J = 1.1 Hz, IH), 7.92 (d, J = 0.7 Hz, IH), 7.72 (d, J = 0.8 Hz, IH), 7.47 (m,2H), 7.43 - 7.38 (m, 2H), 7.37 (m, IH), 7.13 (d, J = 1.1 Hz, IH), 4.82 4.74 (m, 2H), 3.83 (m, 4H), 3.25 (d, J = 11.7 Hz, 2H), 3.10-2.95 (m, 1 H), 2.86 (d, J = 0.7 Hz, 3H), 1.91 (qd, J = 12.7,4.4 Hz, 2H), 1.67 (d, J = 12.5 Hz, 2H). LCMS m/z 507.0 [M+lf.____
161	From S4 - see footnote5 Me °^Me θ H / NVVl /—\ N l| î AJ p F	Οχ 'P-Me f A J3 0^	‘H NMR (400 MHz, Methanol-di) δ 8.02 7.90 (m, 3H), 7.76 7.66 (m, 2H), 7.57 7.47 (m, 2H), 7.45 7.35 (m, 2H), 7.29 (t, J = 1.1 Ηζ,ΙΗ), 7.12 (d, J = 1.2 Hz, IH), 3.87 3.75 (m, 2H), 3.21 (td, J = 11.8, 2.0 Hz, 2H), 3.06 (tt, J = 12.2, 3.5 Hz, IH), 1.89 (d, J = 13.4 Hz, 6H), 1.86 1.55 (ni, 4H). LCMS m/z 488.0 [M+lf.

440

Compound	Method/Product	Boronic acid or ester	'H NMR; LCMS m/z [M+H]+
162	From S4 - See footnote3'4 OH n-n H / NvAN. /—\ A J I VA P F	$OH N-N O O AA	'H NMR (400 MHz, DMSOA) δ 12.60 (s, IH), 7.98 (d, J = 1.2 Hz, IH), 7.93 (d, J = 0.8 Hz, IH), 7.63 (d, J = 0.8 Hz, IH), 7.56 (m, 2H), 7.53 - 7.46 (m, 2H), 7.36 (t, J = 1.1 Hz, IH), 7.02 (d, J = 1.0 Hz, IH), 5.00 (m, IH), 4.28 (t, J = 5.7 Hz, 2H), 3.85 (m, 2H), 3.81 - 3.72 (m, 2H), 3,16 (td, J = 11,7, 2,0 Hz, 2H), 3.08 2.94 (m, IH), 1.75 (qd, J = 12.5, 4.2 Hz, 2H), 1.63 (d, J = 12.9 Hz, 2H). LCMS m/z 446.2 [M+l]+.
163	From S4 - See footnote3 4 V™ H / n-^^A n. J J VA P ^AA^-n λ—7 F	VOH N-N XB„ JD__CJ	'H NMR (400 MHz, DMSOA) δ 12.59 (d, J = 1.3 Hz, IH), 7.9S (t, J = 1.3 Hz, IH), 7.88 (d, J = 0.8 Hz, IH), 7.62 (d, J = 0.7 Hz, IH), 7.60 - 7.53 (m, 2H), 7,49 (m, 2H), 7.32 (t, J = 1.1 Hz, IH), 7.04 (t, J = 0.9 Hz, IH), 4.79 (s, IH), 4.16 (s, 2H), 3.76 (dd, J = 11.4, 4.0 Hz, 2H), 3.14 (t, J = 11.6 Hz, 2H), 3.07 - 2.90 (m, IH), 1.88 - 1.68 (m, 2H), 1.63 (d, J = 12.9 Hz, 2H), 1.15 (s, 6H). LCMS m/z 558.3 [M+l]4.

441

Compound	Method/Product	Boronic acid or ester	'H NMR; LCMS m/z [M+H]’
164	From S4 - See footnote2'3 pO Λ ri n l| [ fl—< o AA/A-N λ/ F	j-o N-N A	lHNMR (400 MHz, MethanoI-c/4) δ 7.96 (mz, 2H), 7.77 (d, J = 0.7 Hz, IH), 7.47 (m, 2H), 7.42 - 7.36 (m, 2H), 7.35 (t, J = 1.1 Hz, IH), 7.10 (d, J = 1.2 Hz, IH), 5.795.64 (m, IH), 5.235.09 (m, 4H), 3.84 (dd, J= 11.5,4.2 Hz, 2H), 3.29-3.21 (m, 2H), 3.02 (tt, J= 12.5, 3.5 Hz, IH), 1.90 (qd, J = 12.5,4.4 Hz, 2H), 1.68 (d, J = 12.8 Hz, 2H). LCMS m/z 542.14 [M+I]+.
165	From S4 - See footnote2'3 HO^/O n-n H ! naa-a /—\ n. ]| [ Va P AA-An x/ F	HO-£° N-N A	“H NMR (400 MHz, Methanol-i/4) δ 7.96 (d, J = 1.1 Hz, IH), 7.87 (d, J = 0.7 Hz, IH), 7.68 (d, J = 0.7 Hz, IH), 7.48 (m, 2H), 7.42 (t, J = 1.1 Hz, IH), 7.41 - 7.35 (m, 2H), 7.09 (d, J = 1.2 Hz, IH), 5.10 (s, 2H), 3.84 (dd, J = 11.6, 4.2 Hz, 2H), 3.29 - 3.20 (m, 2H), 3.05 (ddd, J = 12.4, 8.9, 3.5 Hz, IH), 1.93 (qd, J = 12.6, 4.3 Hz, 2H), 1.67 (d, J = 12.8 Hz, 2H). LCMS m/z 544.17 [M+lf.

442

Compound	Method/Product	Boronic acid or ester	’H NMR; LCMS m/z [M+H]+
166	From S 4 - See footnote2'3 N -b H / N-AwP /Ά N. J L Vf p F	N-N Z	'HNMR (400 MHz, Methanol-t74) δ 7.96 (d, J= 1.1 Hz, IH), 7.83 (d, J = 0.8 Hz, IH), 7.64 (d,J = 0.8 Hz, IH), 7.50-7.44 (m, 2H), 7.39 (m, 2H), 7.32 (t, J = 1.1 Hz, IH), 7.11 (d, J = 1.1 Hz, IH), 4.53 -4.41 (m, 2H), 3.89 - 3.77 (m, 4H), 3.35 (t, J = 7.1 Hz, 2H), 3.24 (t, J = 1L3 Hz, 2H), 3.06 2.92 (m, IH), 2.35 (t, J = 8.1 Hz, 2H), 2.02 (m, 2H), 1.98 - 1.S3 (m,2H), 1.68 (d, J = 13.2 Hz, 2H). LCMS m/z 597.22 [M+l]+.
167	From S4 - See footnote6 -OH H / /---y w. 1! b Vf p F	1 f-0·. Λζ 7 A o ! T	‘H NMR (400 MHz, Methanol-J4) δ 7.95 (s, IH), 7.90 (s, IH), 7.66 (s, IH), 7.46 (m, 2H), 7.42 - 7.33 (m, 3H), 7.08 (m, IH), 3.90 - 3.80 (m, 4H), 3.29 - 3.19 (m, 2H), 3.10 - 2.97 (m, IH), 1.90 (qd, J = 12.6, 4.2 Hz, 2H), 1.66 (m, 8H). LCMS m/z 474.1 [M+l]+.

Two products were obtained in the hydrolysis step. Purification by reversed-phase chromatography (Column: Cl8. Gradient: 10-100 % MeCN in water) afforded compounds 148 and 149.

²' Purification by reversed-phase chromatography (Column: C18. Gradient: 10-100 % MeCN in water with 0.2 % formic acid) afforded the product.

³* The Suzuki coupling step was perfonned by reaction of S4 and the appropriate boronic ester or boronic acid with Pd(PPh₃)₄ catalyst and Na2CO₃. The reaction was performed in a mixture of DMF and 1,4-dioxane at 140 °C under microwave conditions.

⁴’ Purification by reversed-phase HPLC. Method: Cl8 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H₂O with 0.1 % trifluoroacetic acid

ΙΟ

443 ⁵· The Suzuki coupling step was performed using SPhos Pd G3 and K₃PO₄. 2-(4dimethylphosphorylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaboroiane was prepared by coupling 2-(4-iodophenyl)-4,4,5,5-tetramethyl’I,3,2“dioxaborolane and methylphosphonoylmethane using Pd₂(dba)₃. xantphos and NEt₃.

The Suzuki coupling step was performed using Pd(PPh₃)₄ and Na₂CO₃, heating in a microwave at 125 °C pW for 1 hour. Pivaloyl group deprotection was performed using NaOH in éthanol heatîng at 50 °C. Purification by reversed-phase HPLC. Method: Cl 8 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H₂O with 0.1 % trifluoroacetic acid. The product was then triturated with heptane:dichloromethane (8:2) to afford the product 167 2-[4<5-(4-fluorophenyI)-6-tetrahydropyran-4-yl-lH-pyrro1o[2,3f]indazoI-7-yl]pyrazol-l-yI]-2-methyl-propan-l-ol.

Compound168

7-(6-dimethylphosphoryl-3-pyridyl)-5-(4-fiuorophenyl)-6-tetrahydropyran-4-yl-lH15 pyrrolo[2,3 -f]indazole (168)

1.

Pd(OAc)₂

XantPhos

K₃PO₄

O

II

Me । H Me

2. NaOH

Step 1. Synthesis of 7-(6-chloro-3-pyridyl)-5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lHpyrrolo [2,3-f] indazole (C172)

To a mixture of l-[5-(4-fluorophenyl)-7-iodo-6-tetrahydropyran-4-yl-pyrrolo[2,320 f]indazol-l-yl]-2,2-dimethyl-propan-l-one (50 mg, 0.09 mmol), 2-ch loro-5-(4,4,5,5-tetram ethyll,3,2-dioxaboroian-2-yl)pyridine (26 mg, 0.11 mmol), and Pd(PPh₃)₄ (5 mg, 0.004 mmol) in 1,4dioxane (0.6 mL) and DMF (0.6 mL) was added a solution of Na₂CO₃ (136 pL of 2 M, 0.3 mmol). The reaction was heated at 100 °C for 18 hours. Water and dichloromethane were added.

444

The mixture was extracted with dichloromethane (x 3). The organic phases were filtered through a phase separator, combined and the volatiles were evaporated in vacuo. Purification by reversed phase chromatography (Cl8 column. Gradient: 0-40% of CH₃CN in water containing fonnic acid) afforded the product as a white solid. l-[7-(6-chloro-3-pyridyl)-5-(4-fluorophenyl)-65 tetrahydropyran-4-yl-pyrrolo[2,3-f]indazoLl-yl]-2,2-dimethyl-propan-1-one (19.4 mg, 40%). ‘H NMR (400 MHz, Chloroform-d) δ 8.48 (dd, J = 2.4, 0.8 Hz, IH), 8.36 (d, J = 1.0 Hz, IH), 8.07 (d, J = 0.8 Hz, IH), 7.80 (dd, J = 8.1, 2.4 Hz, IH), 7.49 (dd, J = 8.1, 0.8 Hz, IH), 7.44 (ddd, J = 8.8, 5.0, 2.6 Hz, 2H), 7.37-7.31 (m, 2H), 7.13 (d, J = 1.0 Hz, IH), 3.92 - 3.80 (m, 2H), 3.22 (td, J = 11.8, 2.0 Hz, 2H), 2.97 (tt, J = 12.3, 3.5 Hz, IH), 1.85 - 1.69 (m, 2H), 1.69 - 1.59 (m, 2H), 10 1.55(s,9H). LCMS m/z 531.1 [M+l]¹.

Step 2. Synthesis of 7-(6-dimethylphosphoryl-3-pyridyl)-5-(4-fluorophenyl)-6-tetrahydropyran-4yl-1 H-pyrrolo[2,3-f]indazole (168)

Part A. To a mixture of l-[7-(6-chloro-3-pyridyl)-5-(4-fluorophenyI)-6-tetrahydropyran4-yl-pyrrolo[2,3-f]indazol-l-yl]-2,2-dimethyl-propan-l-one (20 mg, 0.037 mmol), K₃PO₄ (25 15 mg, 0.12 mmol), Xantphos (5 mg, 0.009 mmol) and Pd(OAc)₂ (2 mg, 0.009 mmol) in DMF (500 pL) was added methylphosphonoylmethane (9 mg, 0.12 mmol). The mixture was heated at 150 °C for 20 minutes. Water and dichloromethane were added. The mixture was extracted with CH2CI2 (x 3). The organic phases were filtered through a phase separator, combined and the volatiles were evaporated in vacuo. The crude was used as is in the next step, 1-(7-(620 dimethylphosphoryl-3-pyridyl)-5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-pynOlo[2,3-f]indazol1 -yl]-2,2-dimethyl-propan-1 -one.

Part B. To a solution of l-[7-(6-dimethylphosphoryl-3-pyridyl)-5-(4-fluorophenyl)-6tetrahydropyran-4-yI-pyrroio(2,3-f] indazol-i-yl]-2,2-dimethyl-propan-1-one (from part A) in Ethanol (1 mL) was added NaOH (150 pL of 1 M, 0.15 mmol). The réaction was heated at 50 °C 25 for 18 hours. Water and dichloromethane was added. The mixture was extracted with dichloromethane (x 3). The organic phases were filtered through a phase separator, combined and the volatiles were evaporated in vacuo. Purification by reversed-phase HPLC (Method: Cl8 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H₂O with 0.2 % fonnic acid) afforded the product as a white solid. 7-(6-dimethylphosphoryl-3-pyridyl)-5-(430 fluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrroIo[2,3-f]indazole (11 mg, 60%). ^lH NMR (400

MHz, Methanol-A) δ 9.03 - 8.81 (m, IH), 8.19 (ddd, J = 7.9, 5.3, 1.0 Hz, IH), 8.14 (ddd, J = 7.8, 3.6, 2.0 Hz, IH), 7.99 (d, J = 1.0 Hz, IH), 7.59 - 7.49 (m, 2H), 7.46 - 7.37 (m, 2H), 7.31 (t, J = 1.1 Hz, ! H), 7.15 (d, J = 1.1 Hz, IH), 3.81 (dd, J = 10.9, 3.6 Hz, 2H), 3.23 (td, J = 11.3, 3.4 Hz, 2H), 3.07 (tt, J = 11.0, 4.9 Hz, IH), 1.93 (s, 3H), 1.90 (s, 3H), 1.85 - 1.67 (m, 4H). LCMS m/z 35 489.1 [M+l]⁺.

445

Compound 169

4-[5-(4-fluorophenyl)-6-(4-hydroxytetrahydropyran-4-yl)pyrrolo[2,3-f] [l,3]benzothiazol- 7yljbenzoic acîd (169)

Step 1. Synthesis of 6-bromo-5-nitro-l,3-benzothiazole (C174)

Part A. A mixture of 4-bromo-2-fluoro-5-nitro-anîline C173 (5 g, 21.3 mmol) and potassium ethoxycarbothioylsulfanyl (7 g, 43.7 mmol) in DMF (60 mL) was stirred for 1 8 h at 110 °C. Upon cooling to room température, the mixture was diluted with water (200 mL) and concentrated HCl (10 mL). The resulting solid précipitâtes were collected by vacuum filtration, 10 and washed with water to afford 6-bromo-5-nitro-3H-l ,3-benzothiazole-2-thione (6 g, 97%) which was used directly in part B. LCMS m/z 290.0 [M+1 ] \

Part B. To a solution of 6-bromo-5-nitro-3H-l,3-benzothiazole-2-thione (6 g, 97%) in AcOH (60 mL), EtOH (15 mL), THF (15 mL) and water (15 mL) was added Fe (6.6 g, 118.2 mmol). The reaction mixture was heated at 110 °C for 4 h. The reaction mixture was cooled to 15 room température, diluted with EtOAc, and filtered through a layer of Celite®. The filtrate was

446 dried over Na₂SO₄, and concentrated to afford the product, 6-bromo-5-nitro-l,3-benzothiazole (3.8 g, 69%). LCMS m/z 260.0 [M+l]⁺.

Step /.Synthesis of 6-bromo-l,3-benzothiazol-5-amine(CI75)

A solution of 6-bromo-5-nitro-l,3-benzothiazoIe C174 (3.8 g, 14.7 mmol) in MeOH (30 mL) and THF (I0 mL) was cooled to 0 °C. NÎCl₂ (2.5 g, 19.3 mmol) and sodium borohydride (1-6 g, 42.3 mmol) were added to the solution in portions. An additional portion of sodium borohydride (3 g, 79.3 mmol) was added and the mixture stirred for 30 minutes. The reaction was quenched with water, diluted with CH₂C1₂, and filtered through a layer of Celite®. The organic layer was dried over Na₂SO₄, and concentrated. Purification by silica gel chromatography (Gradient: 0-40% EtOAc in heptane) to afford the product. 6-bromo-l,3benzothiazol-5-amine (850 mg, 25%). LCMS m/z 230.0 [M+l]⁺.

Step 3. Synthesis of 6-bromo-N-(4-fluorophenyl)-l,3-benzothiazol-5-amine (C176)

A mixture of 6-biOmo-l,3-benzothiazol-5-amine (170 mg, 0.74 mmol), (4fluorophenyl)boronic acid (200 mg, 1.4 mmol), copper (II) acetate (270 mg, 1.49 mmol) and K2CO3 (210 mg, 1.52 mmol) in DMSO (5 mL) was stirred for 2 days. The mixture was diluted with EtOAc, filtered through a layer of Celite®. The organic layer was then washed with water, dried over Na₂SO₄, and concentrated. Purification by silica gel chromatography (Gradient: 030% EtOAc în heptane) afforded the product. 6-bromo-N-(4-fluorophenyl)-l,3-benzothîazol-5amine (60 mg, 25%). LCMS m/z 323.0 [M+l]⁺.

Step 4. Synthesis of 4-[5-(4-fhiorophenyl)-6-(4-hydroxytetrahydropymn-4-yi)pyrrolo[2,3f][1,3]benzothiazol-7-yl]benzoic acid (169)

To a mixture of 6-bromo-N-(4-fluorophenyl)-l,3-benzothiazoI-5-amine C176 (50 mg, 0.15 mmol), methyl 4-[2-(4-hydroxytetrahydropyran-4-yl)ethynyl]benzoate (73 mg, 0.28 mmol), and N-cyclohexyl-N-methyl-cyclohexanamine (85 pL, 0.40 mmol) was added 1,4dioxane (1.0 mL) and the mixture purged with nitrogen for 5 minutes. Pd(/Bu₃P)₂ (8.5 mg, 0.02 mmol) was added and the reaction flushed with nitrogen. The mixture was heated to 110 °C ovemight. The mixture was concentrated to dryness under reduced pressure, diluted with CH₂C1₂ (10 mL) and washed with water (8 mL) and brine (8 mL). The organic layer was passed through a phase separator and concentrated under reduced pressure. Purification by silica gel chromatography (Gradient: 0-80% ethyl acetate in heptane) afforded the product which was used in the subséquent hydrolysis step. methyl 4-[5-(4-fluorophenyl)-6-(4-hydroxytetrahydropyran-4yl)pyrrolo[2,3-f][l,3]benzothîazol-7-yl]benzoate (28 mg, 36%). LCMS m/z 503.0 [M+l].

To a solution of methyl 4-[5-(4-fluorophenyl)-6-(4-hydroxytetrahydropyran-4yI)pyrrolo[2,3-f][l,3]benzothiazol-7-yl]benzoate C177 (28 mg, 36%) in THF (1 mL) and MeOH (1 mL) was added NaOH (1 mL of 1 M, 1.0 mmol). The mixture was stirred for 2 h at 447 room temperature. The reaction mixture was adjusted to pH = 3, then concentrated. Purification by silica gel chromatography (Gradient: 0-5% MeOH în dichloromethane), and then by reversed phase chromatography (Cl 8 column. Gradient: 10-100% CH₃CN in H₂O containing 0.2 % fonnic acid) afforded the product. 4-[5-(4-fluorophenyl)-6-(4-hydroxytetrahydropyran-45 yl)pyrrolo[2,3-f][l,3]benzothiazol-7-yl]benzoic acid (7.2 mg, 9%). ^lH NMR (400 MHz,

Methanol-rf₄) S 9.07 (s, IH), 8.24 - 8.07 (m, 2H), 7.65 - 7.49 (m, 6H), 7.39 - 7.28 (m, 3H), 3.66 (td, J = 11.8, 2.0 Hz, 2H), 3.57 - 3.45 (m, 2H), 2.09 - 1.92 (m, 2H), 1.77 - 1.62 (m, 2H). LCMS m/z 489.0 [M+l]⁺.

Compound 170

4-/6-(3,6-dihydro-2H-pyran-4-yî)-5-(4-fluorophenyl)pyrrola[2,3-J] / 1,3] benzothiazol- 7yljbenzoic acid (170)

Step 1. Synthesis of methyl 4-/6-(3,6-dihydro-2H-pyran-4-yl)-5-(4-fluorophenyl)pyrrolo[2,315 fj [1,3] benzothiazol-7-yl] benzoate (C178)

A mixture of 6-bromo-N-(4-fluorophenyI)-l,3-benzothiazol-5-amine Cl76 (60 mg, 0.19 mmol), methyl 4-[2-(4-hydroxytetrahydropyran-4-yljethynyl]benzoate Cl 58 (75 mg, 0.29

448 mmol), and N-cyclohexyl-N-methyl-cyclohexanamine (l 10 pL, 0.51 mmol) in 1,4-dioxane (1.2 mL) was purged with nitrogen for 5 min. Pd(tBu₃P)₂ (10 mg, 0.02 mmol) was added, and the mixture was flushed with further nitrogen. The reaction vial was sealed and the mixture heated to 110 °C ovemight. The reaction was then concentrated to near dryness under reduced 5 pressure. The mixture was diluted with CH₂C1₂ (10 mL) and washed with water/brine (8 mL).

The organic layer was passed through a phase separator and concentrated under reduced pressure. Silica gel chromatography (Gradient: 0-80% ethyl acetate in heptane) afforded two products C177 methyl 4-[5-(4-fluorophenyl)-6-(4-hydroxytetrahydropyran-4-yl)pyrrolo[2,3f][l,3Jbenzothiazol-7-yl]benzoate (57 mg, 61%), LCMS m/z 503.0 [M+lf and methyl 4-[610 (3,6-dihydro-2H-pyran-4-yl)-5-(4-fluorophenyl)pynOlo[2,3-f][1,3]benzothiazol-7-yl]benzoate

Cl78 (20 mg, 22%), LCMS m/z 485.0 [M+l]^d. Cl78 was used in the subséquent step without further purification.

Step 2. Synthesis of 4-[6-(3,6-dihydro-2H-pyran-4-yl)-5-(4-fluorophenyl)pyrrolo[2,3J][l,3]benzothiazol-7-yl]benzoic acid (170)

To a solution of methyl 4-(6-(3,6-dihydro-2H-pyran-4-yl)-5-(4-fluorophenyl)pyrrolo[2,3q[l,3]benzothiazol-7-yl]benzoate C178 (15 mg, 0.031 mmol) in MeOH (2 mL) was added NaOH (300 pL of 1 M, 0.30 mmol). The reaction was stirred for 1 h, then the mixture was adjusted to pH = 2. Purification by reversed phase chromatography (Cl8 column. Gradient: 1090% CH₃CN in H₂O contain în 0.2% formic acid) afforded 4-[6-(3,6-dihydro-2H-pyran-4-yl)-520 (4-fluorophenyl)pyrrolo[2,3-f][l,3]benzothiazol-7-yl]benzoic acid 170 (5.1 mg, 33%). ‘H NMR (400 MHz, DMSO-J₆) Ô 9.20 (s, IH), 8.07 (d, J = 8.0 Hz, 2H), 7.71 (s, IH), 7.65 - 7.52 (m, 7H), 7.19 (s, IH), 5.17 (s, IH), 3.49 (t, J= 11.4 Hz, 2H), 1.93 - 1.78 (m, 2H), 1.61 (d, J = 13.1 Hz, 2H). LCMS Wz471.8 [M+l]⁺.

Compound 171

N- (1,1 -dimelhyl-2-methylsulfonyl-ethyl)-4-[5-(4fluorophenyl)-6-tetrahydropyran-4-yl-1Hpyrrolo]2,3-f]indazol-7-yl]benzamide (171)

449

Compound 171 was prepared from compound 33 and 2-methyl-l(methylsulfonyl)propan-2-amine by an amide coupling reaction with HATU and DIPEA as described for compound 145. NMR (400 MHz, DMSO-rf₆) δ 12.60 (s, 1 H), S.25 (s, IH), 8.03 - 7.91 (m, 2H), 7.66 - 7.56 (m, 4H), 7.51 (t, J = 8.7 Hz, 2H), 7.21 (t, J = 1.1 Hz, IH), 7.08 (d, J = 1.1 Hz, IH), 3.87 (s, 2H), 3.77 - 3.67 (m, IH), 3.37 (s, 3H), 3.09 (td, J = 11.3, 4.4 Hz, 2H), 3.00 (s, 3H), 1.68 (td, J = 9.7, 8.4, 3.4 Hz, 4H), 1.61 (s, 6H). LCMS m/z 589.2 [M+H]⁺.

Compound 172

4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3-f]indazol-7-yl]-N-(2methylsidfonylelhyl)benzamide (172)

Compound 172 was prepared from compound 33 and 2-(methylsulfonyl)ethan-l-amine by an amide coupling reaction with HATU and DIPEA as described for compound 145.

‘H NMR (400 MHz, DMSCMs) δ 12.59 (s, IH), 8.84 (t, J = 5.6 Hz, IH), 8.09 - 7.91 (m, 2H), 7.62 (d, J = 8.4 Hz, 4H), 7.51 (t, J = 8.7 Hz, 2H), 7.23 (s, IH), 7.08 (d, J = 1.1 Hz, 1 H), 3.81 3.67 (m, 6H), 3.44 (d, J = 6.8 Hz, 2H), 3.09 (s, 4H), 2.99 (s, IH), L66 (d, J = 3.1 Hz, 4H). LCMS m/z 561.1 [M+H],

Compound 173 [4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3-j]indazol-7-yl]phenyl]-(3methylsulfonylazetidin-l-yl)methanone (173)

450

Compound 173 was prepared from compound 33 and 3-(methylsulfbnyl)azetidme by an amide coupling reaction with HATU and DIPEA as described for compound 145.

'H NMR (400 MHz, DMSO-4) δ 12.59 (s, IH), 8.00 (d, J = 1.1 Hz, IH), 7.85 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 8.2 Hz, 4H), 7.51 (t, J = 8.7 Hz, 2H), 7.27 (s, IH), 7.07 (d, J = 1.1 Hz, IH), 4.79 5 (s, IH), 4.59 (d, J = 9.5 Hz, IH), 4.40 (d, J = 6.3 Hz, 2H), 4.31 (s, IH), 3.83 -3.70 (m, 2H), 3.11 (s, 5H), 3.02 (s, IH), 1.77 - 1.59 (m, 4H). LCMS m/z 573.2 [M+H]⁺.

Compound 174 & Compound 175

7-[4-[ethoxy/methyl)phosphoryl]phenyl] -5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lHpyn'olo[2,3-f]indazole /174) and [4-[5-(4-jluorophenyl)-6-tetrahydropyran-4-yl~lH0 pyrrolo[2,3-f] indazol- 7-yl]phenyl]-methyl-phosphinic acid /175)

ci79 C180

451

Synthesis of 2-[4-[ethoxy(melhyl)phosphoryl]phenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (C180)

Diethoxy(methyl)phosphane (180 mg, L32 mmol) was added to a mixture of 2-(4iodophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (330 mg, l.O mmol) and NiCl₂ (13 mg, 0,10 mmol). The mixture was purged with nitrogen for 5 min. The reaction mixture was stirred at 170 °C for 2 h. Purification by silica gel chromatography (Gradient: 0-8 % MeOH in dichloromethane) afforded the product as a colorless oil 2-[4[ethoxy(methyl)phosphoryl] phenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane C180 (70 mg, 23%), LCMS m/z 33 LO [M+l]\ The boronic acid product [4[ethoxy(methyl)phosphoryl] phenyl] boronic acid (70 mg, 31%) was also obtained. C181 was used în the subséquent step without further purification.

Synthesis of 7-[4-[ethoxy(methyl)phosphoryl]phenyl] -5-(4-fluorophenyl)-6-tetrahydropvran-4yl- IH-pyrrolo]2,3-f] indazole (174)

Part A. 1,4-dioxane (500 pL) and water (100 pL) were added to a vial charged with 1[5-(4-fluorophenyl)-7-iodo-6-tetrahydropyran-4-yl-pyrroIo[2,3-f] indazol-l-yl]-2,2-dimethylpropan-1 -one S4 (57 mg, 0.10 mmol), 2-[4-[ethoxy(meth yl)phosphoryl] phenyl]-4,4,5,5tetramethyl-1,3,2-dioxaborolane C180 (48 mg, 0.15 mmol), and K₃PO₄ (70 mg, 0.33 mmol). The solution was purged with N₂ for 10 min. SPhos Pd G3 (10 mg, 0.013 mmol) was added and the reaction was heated to 80 °C for 30 min. Water (5 mL) and dichloromethane (5 mL) were added, and the mixture was passed through a phase separator. The organic phase was concentrated and purified by silica gel chromatography (Gradient: 0-5 % MeOH in dichloromethane) to afford the product C181 as a white solid. l-[7-[4[ethoxy(methyl)phosphoryl] phenyl] -5-(4- fluorophenyl)-6-tetrahydrop yran-4-yl-pyrrolo [2,3 f]indazol-l-yl]-2,2-dimethyl-propan-l-one (55 mg, 88%). LCMS m/z 602.0 [M+l]+.

Part B. To a solution ofl-[7-[4-[ethoxy(methyl)phosphoryl]phenyl]-5-(4-fluorophenyl)6-tetrahydropyran-4-yl-pyrrolo[2,3-fJindazol-l-y]]-2,2-dimethyl-propan-l-one Cl 81 (55 mg) in MeOH (1.5 mL) and THF (1.5 mL) was added NaOH (750 pL of 1 M, 0.75 mmol) and the mixture stirred for 1 h. The reaction was then concentrated and adjusted to pH = 2. The mixture contained both compound 174 and compound 175. The solution was extracted with dichloromethane and separated on a phase separator. The organic phase was purified by silica gel chromatography (Gradient: 0-10% MeOH in dichloromethane) to afford the product 7-[4[ethoxy(methyl)phosphoryl] phenyl]-5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-IH-pyrrolo [2,3f]indazole 174 (4.2 mg, 8%), LMS m/z 518.14 [M+1]C ^lH NMR (400 MHz, Chloroform-d) δ 10.04 (s, IH), 8.06 (d, J = 1.1 Hz, IH), 8.01 - 7.90 (m, 2H), 7.72 - 7.63 (m, 2H), 7.52 - 7.44 (m, 2H), 7.40 (t, J= 1.1 Hz, IH), 7.37 - 7.30 (m, 2H), 7.15 (d, J = 1.1 Hz, IH), 4.22 (m, IH), 4.11 452

3.96 (m, IH), 3.88 (dd, J= H.6,4.1 Hz, 2H), 3.25 (t, J = 11.7 Hz, 2H), 3.05 (ddd, J = 12.4, 8.9, 3.4 Hz, IH), 1.99 - 1.71 (m, 5H), 1.66 (d, J = 11.9 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H). An unseparated mixture of compound 174 and 175 was also obtained, and used in the subséquent step without further purification.

Synthesis of [4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3-f]indazol- 7yl]phenyl] -methyl-phosphinic acid (175)

To a mixture of compound 174 and 175 in dichloromethane (2 mL) was added trimethylsilyl bromide (100 pL, 0.76 mmol). The reaction was allowed to stir at room température for 1 h. The mixture was concentrated and purified by reversed phase chromatography (Cl8 column. Gradient: 10-90 % MeCN in water containing 0.2 % formic acid) to afford the product 175. *H NMR (400 MHz, Chloroform-r/) Ô 8.15 - 7.89 (m, 4H), 7.58 (d, J = 7.5 Hz, 2H), 7.41 (d, J = 10.4 Hz, 3H), 7.29 (m, 2H), 7.11 (d, J = 1.1 Hz, IH), 3.83 (d, J = 10.9 Hz, 2H), 3.21 (t, J = 11.6 Hz, 2H), 3.09 - 2.90 (m, 2H), 1.82 (d, J = 14.5 Hz, 4H), 1.59 (d, J = 12.9 Hz, 2H). LCMS m/z 490.0 [M+l]⁺.

Compound 176

4-(5-(4 -fiuorophenyl)-6-(4-hydroxytetrahydro-2H-pyran-4-yl)-l,5-dihydropyrrolo[2,3f]indazol-7-yl)benzoic acid (176)

Step 1. Synthesis of l-(benzenesulfonyl)-6-bromo-N-(4-fluorophenyl)indazol-5-amine (Cl82)

453

To a suspension of 6-bromo-N-(4-fluorophenyl)-lH-indazol-5-amine Cl 17 (2 g, 6.5 mmol) in THF (55 mL) at 1 °C (ice-water bath) was added KOtBu (7.2 mL of 1 M, 7.2 mmol). After ~10 min, benzenesulfonyl chloride (1.11 mL, S.7 mmol) was added and the mixture stirred for 60 min in cooling bath. The reaction was quenched with water (10 mL), stirred for 5 min. The mixture was then extracted with ethyl acetate (100 mL) and the organic layer dried over with sodium sulfate. Purification by silica gel chromatography (0-100% ethyl acetate in heptane) afforded the product C182 l-(benzenesulfonyl)-6-bromo-N-(4-fluorophenyl)indazol-5-amine (2.36 g, 81%). LCMS m/z 446.1 [M+l]⁺. ^fH NMR. showed the product contained a mixture of the two indazole regîosiomers with the phenyl sulfonyl group on NI and N₂.

Step 2. Synthesis of methyl 4-[l-(benzenesulfonyl)-5-(4-fluorophenyl)-6-(4hydroxytetrahydropyran-4-yl)pyrrolo[2,3-f/indazol-7-yl]benzoate (C183)

1,4-Dioxane (8.2 mL) was added to a mixture of l-(benzenesulfonyI)-6-bromo-N-(4fluorophenyl)indazol-5-amine (394.6 mg, 0.88 mmol) C182, methyl 4-[2-(4hydroxytetrahydropyran-4-yl)ethynyl]benzoate C183 (420 mg, 1.6 mmol), and N-cyclohexyl-Nmethyl-cyclohexanamine (478 pL, 2.2 mmol). The mixture was evacuated and flushed with nitrogen. Pd(PtBu₃)₂ (49 mg, 0.096 mmol) was added and the reaction evacuated and flushed with nitrogen an additional time. The reaction vial was sealed and heated to 80 °C ovemight. The mixture was concentrated to dryness, diluted with dîchloromethane (10 mL) and washed with water/brine (8 mL). The organic phase was passed through a phase separator and concentrated to dryness under reduced pressure. Purification by silica gel chromatography (Gradient: 0-100% ethyl acetate in heptane) afforded the product C183 (531.8 mg, 94%). ’H NMR (300 MHz, DMSO-d6) δ 8.47 (d, J = 0.8 Hz, IH), 8.18 (d, J = 8.3 Hz, 2H), 7.72 - 7.61 (m, 6H), 7.59 - 7.49 (m, 4H), 7.40 (t, J = 8.7 Hz, 2H), 7.06 (d, J = 1.0 Hz, IH), 5.22 (s, IH), 3.94 (s, 3H), 3.51 - 3.39 (m, 4H), 1.90 - 1.78 (m, 2H), 1.58 (d, J = 12.9 Hz, 2H). LCMS m/z 626.2 [M+l]⁺.

Step 3. Synthesis of 4-(5-(4-fluorophenyl)-6-(4-hydroxytetrahydro-2H-pyran-4-yl)-l,5dihydropyrrolo[2,3-f]indazol-7-yl)benzoic acid (J 76)

To a solution of methyl 4-[ i-(benzenesulfonyl)-5-(4-fluorophenyl )-6-(4hydroxytetrahydropyran-4-y])pyrrolo [2,3-f]indazol-7-yl] benzoate (44 mg, 0.07 mmol) in methanol (I mL) and THF (1 mL) was added NaOH (700 pL of 1 M, 0.7 mmol) and the mixture was stirred for 2 hours at 65°C. The mixture was Concentrated to dryness under reduced pressure. EtOAc was added and the mixture washed with IM HCL The organic layers were dried over MgSO₄, fïltered and concentrated under reduced pressure. Purification by silica gel chromatography (Gradient: 0-10 % MeOH in dîchloromethane) afforded the product (14.4 mg, 44%).

454 ’Η NMR (300 MHz, DMSO-<4) δ 13.03 (s, IH), 12.51 (s, IH), 8.13 - 8.03 (m, 2H), 7.98 (d, J = 1.0 Hz, IH), 7.64 - 7.52 (m, 4H), 7.40 (t, J = 8.8 Hz, 2H), 6.97 - 6.88 (m, 2H), 5.13 (s, IH), 3.54 - 3.37 (m, 4H), 1.85 (td, J = 12.7, 12.2, 5.2 Hz, 2H), 1.59 (d, J = 13.0 Hz, 2H). LCMS m/z 472.2 [M+lf.

Compound 177

4-(6-(1 -cyano-2-melhylpropan-2-yl)-5-(2-methylpyridin-4-yl)-1,5-dihydropyrrolo[ 2,3 f] indazol-7-yl)benzoic acid (177)

Compound 177 was prepared in two steps from Cl84 by N-arylation wîth 2-methyl 4iodopyridine, then Larock cyclization with C147 as described for the préparation of compound 125. ’H NMR (400 MHz, Methanol-^) δ 8.74 (d, J = 5.3 Hz, 1 H), 8.23 - 8.14 (m, 2H), 7.98 (s, IH), 7.69 - 7.62 (m, 2H), 7.58 (d, J = 1.9 Hz, IH), 7.52 - 7.46 (m, IH), 7.07 - 7.00 (m, 2H), 2.71 (s, 3H), 2.59 (s, 2H), 1.36 (s, 6H). LCMS m/z 450.28 [M+Hf

Compounds 178-182

Compounds 178-182 (Table 13) were prepared from alkyne C147 and the appropriate aryl aniline in two steps using the method described for the préparation of compound 125. Aryl anilines were prepared from C184 or C89 and the appropriate aryl halide by N-arylation using

455

Buchwald conditions. Alternatively, aryl anilines were prepared from C95 as described for the préparation of compound C96.

Table 13. Method of préparation, structure, physicochemical data for compounds 178-183

Compound	Structure	Aryl lodide or Aniline	lH NMR; LCMS m/z [M+H]'
1781	H	Z Il o t A/F z AA	^N- .OMe M 1	‘H NMR (400 MHz, Methanol-A) δ 8.43 (dd, J = 5.4, 0.6 Hz, IH), 8.23 - 8.13 (m, 2H), 7.98 (d, J =1.2 Hz, 1 H), 7.65 (d, J = 7.6 Hz, 2H), 7.16 (dd, J = 5.4, 1.8 Hz, IH), 7.07 (d, J = 1.1 Hz, IH), 7.05 (dd, J = 1.8, 0.6 Hz, IH), 7.00 (t, J = 1.1 Hz, IH), 4.05 (s, 3H), 2.61 (s, 2H), 1.37 (mz, 6H). LCMS m/z 466.22 [M+H]+.
1792	H O	Οχ JrVV Fn \ F	n-Vf ï J	'H NMR (300 MHz, DMSO-<4) δ 13.2512.84 (bs, IH), 12.59 (s, IH), 8.64 (d, J = 1.1 Hz, IH), 8.11 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 1.0 Hz, IH), 7.84 (d, J = 5.6 Hz, IH), 7.70-7.58 (m, 2H), 7.18 (d, J =1.1 Hz, IH), 6.94-6.85 (m, IH), 2.88 (s, 2H), 2.47 (d, J =1.6 Hz, 3H), 1.18 (s, 6H). LCMS m/z 468.21 [M+H]'.

456

Compound	Structure	Aryl lodide or Aniline	Ή NMR; LCMS m/z [M+Hf
180'	H N x J.	HO fS CA F	f	ï T 'F	'HNMR (400 MHz, Methanol-cb) δ 8.15 (d, J = 8.5 Hz, 2H), 8.10 (dd, J = 5.6, 2.7 Hz, IH), 7.97 (d, J = 1.0 Hz, IH), 7.967.89 (m, IH), 7.67 (t, J = 8.8 Hz, 1 H), 7.647.57 (m, 2H), 7.00 (t, J = 1.1 Hz, IH), 6.97 (d, J = 1.2 Hz, 1 H), 2.59 (s, 2H), 1.33 (s, 6H). LCMS m/z 478.32 [M+H]+.
181'	H N \ J.	HO fS AîAA CA F	-O A--=N OZ	R. V	OB.0H OH	'HNMR (400 MHz, Methanol-c/4) δ 8.22 8.13 (m, 2H), 8.01 (d, J = 1.1 Hz, IH), 7.67 7.58 (m, 2H), 7.39 (dd, J = 11.1, 8.5 Hz, 1 H), 7.29 (dd, J = 7.6, 2.4 Hz, IH), 7.16 (ddd, J = 8.5, 3.9, 2.4 Hz, IH), 7.01 (d, J = 1.1 Hz, 1 H), 6.98 (t, J = 1.1 Hz, IH), 3.90 (s, 3H), 2.69 - 2.49 (m, 2H), 1.36 (d, J = 6.9 Hz, 6H). LCMS m/z 483.37 [M+H]+.
1823	H NZ NV	0 ÇA AAA VA F	OH -=N	i	'H NMR (300 MHz, DMSO-Jô) δ 13.06 (s, IH), 12.52 (s, IH), 8.15-8.05 (m, 2H), 7.99 (d, J= LO Hz, IH), 7.67- 7.58 (m, 2H), 7.54 (d,J = 7.2 Hz, 1 H), 7.48 - 7.40 (m, 2H), 6.95-6.81 (m, 2H), 2.63 (s, 2H), 2.36 (d, J = 1.9 Hz, 3H), 1.26 (d, J = 2.0 Hz, 6H). LCMS m/z |

457

Compound	Structure	Aryl lodide or Aniline	'H NMR; LCMS m/z [M+H]+
			467.36 [M+H]+.

^r Prepared from C184.

^:· Prepared from C95.

³' Prepared from C89.

Compound 183

3-(7-(6-(dimethylphosphoryl)-5-methylpyridin-3-yl)-5-(4-fluoro-3-methoxyphenyl)-l,5dihydropyrrolo[2,3-f]indazol-6-yl)-3-methylbutanenitrile (183)

Compound 183 was prepared from C189 and C188 using the method described for the préparation of compound 125. LCMS m/z 530.16 [M+H]⁺.

Compound184

4-[6-(2-methoxy-1,1 -dimethyl-ethyl)-5-phenyl-1 H-pyrrolo[2,3-f]indazol-7-yl]benzoic acid

458

Compound 184 was prepared by réduction of compound 112 using the method described for the préparation of compound 102. 'H NMR (300 MHz, DMSO-î/ô) δ 12.99 (s, IH), 12.46 (s, IH), 8.12-8.01 (m, 2H), 7.95 (d, J = 1.0 Hz, 1 H), 7.70 - 7.49 (m, 7H), 6.88 - 6.82 (m, IH), 6.79 (d, J = 1.1 Hz, IH), 3.05 (s, 2H), 3.00 (s, 3H), 1.11 (s, 6H). LCMS m/z 440.25 [M+H]⁺.

Compound 185

4-(5-phenyl-6-tetrahydropyran-4-yl-lH-pyrrolo[2,3-f] indazol-7-yl)benzoic acid (185)

Compound 185 was prepared from compound 33 using the réduction method described for the préparation of compound 102. ¹H NMR (300 MHz, DMSOA) δ 12.99 (s, 1 H), 12.58 (s, 1 H), 8.16 - 8.08 (m, 2H), 8.00 (d, J = 1.0 Hz, IH), 7.75 - 7.60 (m, 5H), 7.60 - 7.52 (m, 2H), 7.29 7.24 (m, IH), 7.06 (d, J = 1.1 Hz, IH), 3.77 - 3.67 (m, 2H), 3.14 - 2.96 (m, 3H), 1.77 - 1.59 (m, 4H). LCMS m/z 438.27 [M+H]’.

Compounds 186-202

Compounds 186-202 (Table 14) were prepared from Cl 18 or C117 and the appropriate alkyne, as described for the préparation of compound 125 (Larock cyclization method). Alkynes were prepared from C186 and the appropriate aryl halide as described for the préparation of compound C188. In some examples, compounds were prepared b y Suzuki coupling from 3-[l(2,2-dimethylpropanoyl)-5-(4-fluorophenyl)-7-iodo-pyrrolo[2,3-f]indazol-6-yl]-3-methyIbutanenitrile (see examples 189 and 192 and 195).

Table 14. Method ofpréparation, structure and physicochemical data for compounds 186-202

Compound	Method/Product	lH NMR; LCMS m/z [M+Hf
186	As for compound 125	NMR (400 MHz, DMSO-î/6) δ 13.40 (s, IH), 12.57 (s, IH), 8.01 (d, J = 1.0 Hz, IH), 7.95 (dd, J = 7.9, 1.6 Hz, IH), 7.87 (dd, J = 9.8, 1.6 Hz, IH), 7.74 - 7.65 (m, 2H), 7.65 - 7.58 (m, IH), 7.54 (tt, J = 8.9, 3.1 Hz, 2H), 6.89 (d, J = 1.1 Hz, IH), 6.88 - 6.86 (m, IH), 2.64 (d, J = 2.7 Hz, 2H), 1.26 (d, J = 3.4 Hz, 6H). LCMS m/z

459

Compound	Method/Product	!H NMR; LCMSm/z [M+H]+
	Ox y-oH h y-7 vX ΤΧΧ F	471.275 [M+H]+.
187	As for compound 125 CL y-oH C/F H /^ €îd V N x— F	'H NMR (400 MHz, DMSO-î/6) δ 13.37 (s, IH), 12.57 (s, IH), 8.06 - 7.97 (m, 2H), 7.68 - 7.58 (m, 2H), 7.58 - 7.48 (m, 2H), 7.48 - 7.36 (m, 2H), 6.93 (t, J = 1.1 Hz, IH), 6.89 (d, J = 1.1 Hz, IH), 2.66 (s, 2H), 1.26 (s, 6H). LCMS m/z 471.23 [M+H]+.
188	As for compound 125 HO / ° \ jA oA // h y— ΑΓΑ Q ~ F	‘H NMR (300 MHz, DMSO-^) δ 13.18 (s, IH), 12.54 (s, IH), 7.99 (d, J = 1.0 Hz, IH), 7.96 - 7.83 (m, 2H), 7.74 - 7.65 (m, IH), 7.63 - 7.47 (m, 3H), 6.86 (d, J = l.l Hz, IH), 6.83 (t, J = 1.1 Hz, IH), 3.90 (s, 3H), 2.62 (s, 2H), 1.24 (d, J = 6.8 Hz, 6H). LCMS m/z 484.28 [M+H]+.
1891	Suzuki coupling as for compound 6 Xp'O θ H A. I OL-XAC A F	‘H NMR (400 MHz, Methanol-d4) δ 8.01 - 7.91 (m, 311), 7.77 - 7.71 (m, 2H), 7.59 (m, 2H), 7.42 (m, 2H), 6.96 (t, J = 1.1 Hz, IH), 6.92 (d, J = 1.2 Hz, IH), 2.58 (s, 2H), 1.90 (d, J = 13.4 Hz, 6H), 1.32 (s, 6H); ‘H NMR (400 MHz, Methanol-y) δ 8.02 - 7.90 (m, 3H), 7.74 (dd, J = 8.2, 2.6 Hz, 2H), 7.65 - 7.55 (m, 2H), 7.42 (m, 2H), 6.96 (t, J = 1.2 Hz, IH), 6.92 (d, J = 1.2 Hz, IH), 2.58 (s, 2H), 1.91 (s, 3H), 1.88 (s, 3H), 1.32 (s, 6H). LCMS m/z 485.335 [M+H]+.
190	As for compound 125	‘H NMR (400 MHz, Methanol-e/^) S 7.99 (d, J = 0.7 Hz, IH), 7.94 (d, J = 1.1 Hz, |

460

Compound	Method/Product	'H NMR; LCMSm/z [M+H]+
	HO— zNN yjj H / n-^-a /—=n χΧ XXX '•ΆΑν i F	IH), 7.66 (d, J = 0.7 Hz, IH), 7.57 - 7.48 (m, 2H), 7.43 - 7.34 (m, 2H), 7.18 (t, J = 1.1 Hz, IH), 6.91 (d, J = 1.1 Hz, IH), 2.68 (s, 2H), 1.95 (s, 6H), 1.35 (s, 6H). LCMS m/z 485.4 [M+H]+.
Ï91	As for compound 125 H2N yo H / n M i\A Ô F	'H NMR (400 MHz, DMSO-î/6) δ 12.54 (s, IH), 8.14 (s, IH), 7.99 (s, IH), 7.93 (d, J = 7.4 Hz, IH), 7.81 (d, J = 7.4 Hz, IH), 7.76 (s, IH), 7.69 (t, J = 6.5 Hz, IH), 7.62 - 7.48 (m, 3H), 6.86 (s, IH), 6.83 (s, IH), 3.95 (s, 3H), 2.62 (s, 2H), 1.24 (d, J = 8.6 Hz, 6H). LCMS m/z 483.37 [M+H]+.
1921	Suzuki coupling as for compound 6 Jp-0 n-X // y H Γ N—Ax I ATA X--=N F	’H NMR (400 MHz, Méthanol-^) δ 8.98 - 8.87 (m, IH), 8.23 - 8.11 (m, 2H), 7.97 (d, J = 1.0 Hz, IH), 7.61 (m, 2H), 7.44 (m, 2H), 6.96 (t, J = 1.1 Hz, IH), 6.95 (d, J = 1.2 Hz, IH), 2.61 (s, 2H), 1.92 (dd, J = 13.7, 6.0 Hz, 6H), 1.31 (s, 6H). LCMS m/z 486.25 [M+H]+.
193	Suzuki coupling as for compound 6 KI — .OH yN-yf \A ο H / A ÏX_ ^AA \-ΞΝ F	’H NMR (400 MHz, Méthanol-^) δ 7.93 (d, J = 1.1 Hz, IH), 7.81 (d, J = 0.7 Hz, IH), 7.62 (d, J = 0.7 Hz, IH), 7.57 - 7.48 (m, 2H), 7.46 - 7.33 (m, 2H), 7.26 (t, J = 1.1 Hz, IH), 6.90 (d, J = 1.2 Hz, IH), 4.96 (s, 2H), 2.72 (s, 2H), 1.37 (s, 6H). LCMS m/z 457.36 [M+H]+.
194	Compound 1252	‘H NMR (400 MHz, Méthanol-^) δ 7.97 (d, J = 1.0 Hz, IH), 7.87 (d, J = 3.7 Hz,

461

Compound	Method/Product	lH NMR; LCMS m/z. [M+H]+
	OH OA sO H / N-AA-A 1 kX F	IH), 7.64 - 7.51 (m, 2H), 7.49 - 7.35 (m, 2H), 7.25 (d, J = 3.7 Hz, IH), 7.19 (t, J = 1.1 Hz, IH), 6.94 (d, J = 1.1 Hz, IH), 2.67 (s, 2H), 1.41 (s, 6H). LCMS m/z 459.31 [M+Hf.
1951	Suzuki coupling as for compound 6 O^OH __/'Nz \ H / na+A 1 ΑΛη AAA^-N x-=N F	’H NMR (400 MHz, Methanol-rf4) δ 7.94 (d, J = 1.1 Hz, IH), 7.84 (s, IH), 7.63 (ddd, J = 11.3, 4.9, 2.6 Hz, IH), 7.47 (ddd, J = 7.6, 4.9, 2.6 Hz, IH), 7.44 7.34 (m, 2H), 7.09 (t, J = 1.1 Hz, IH), 6.91 (d, J = 1.2 Hz, IH), 2.76 (d, J = 17.0 Hz, IH), 2.62 (d, J = 16.9 Hz, IH), 2.15 (s, 3H), 1.91 (d, J = 8.6 Hz, 6H), 1.38 (s, 3H), 1.33 (s, 3H). LCMS m/z 499.4 [M+H]+.
196	As for compound 125 /X h '/ νΆΑα i nA £>A '1 '—$N Φ F	lH NMR (400 MHz, Methanol-^) Ô 8.76 (s, IH), 8.07 (d, J = 5.8 Hz, IH), 8.01 (d, J = 1.0 Hz, IH), 7.74- 7.66 (m, IH), 7.60 (m, IH), 7.44 (m, 2H), 6.96 (d, J = 1.1 Hz, IH), 6.85 (d, J = 1.1 Hz, IH), 2.59 (m, 2H), 2.37 (s, 3H), 1.90 (dd, J = 13.7, 6.3 Hz, 6H), 1.29 (s, 6H). LCMS m/z 500.35 [M+H]+.
197	As for compound 125 / 7îo l'A. V# H / 7 X W x--=N F	‘H NMR (400 MHz, Methanol-^) δ 8.74 - 8.64 (m, IH), 7.99 (d, J = 1.1 Hz, IH), 7.93 - 7.87 (m, IH), 7.67 - 7.54 (m, 2H), 7.52 - 7.35 (m, 2H), 6.97 (t, J = 1.1 Hz, IH), 6.95 (d, J = 1.1 Hz, IH), 2.88 - 2.76 (m, 3H), 2.60 (s, 2H), 1.96 (dd, J = 13.5, 6.0 Hz, 6H), 1.31 (s, 6H). LCMS m/z 500.34 [M+H] 7
198	As for compound 125	lH NMR (400 MHz, Methanol-^) δ 9.12 (d, J = 5.9 Hz, IH), 8.53 - 8.40 (m, IH),

462

Compound	Method/Product	!H NMR; LCMS m/z [M+H]+
	r zi W FV-z J Z TV/XXI/ r\~ TL III ° z	8.00 (m, 2H), 7.68 - 7.56 (m, 2H), 7.47 7.41 (m, 2H), 7.15 (s, IH), 7.00 (d, J = 1.2 Hz, IH), 2.77 (s, 2H), 1.98 (d, J = 13.6 Hz, 6H), 1.33 (s, 6H). LCMS m/z 486.39 [M+H]\
199	As for compound 125 / fo N=\ AJ H / NCXXVr X--ΞΞΝ 0 F	lH NMR (400 MHz, Methanol-^) δ 8.01 (m, 2H), 7.86 - 7.78 (m, 0.5H), 7.70 (m, IH), 7.59 (m, IH), 7.52 - 7.36 (m, 2.5H), 6.98 (d, J = 1.2 Hz, IH), 6.87 (s, IH), 2.59 (d, J = 4.6 Hz, 2H), 2.51 (s, 3H), 1.91 (dd, J = 13.7, 9.9 Hz, 6H), 1.29 (d, J = 1.8 Hz, 6H). LCMS m/z 500.35 [M+H]0
200	As for compound 125 °P0 A rT £0-0 0 F	*H NMR (400 MHz, Methanol-^) δ 8.67 (s, IH), 7.98 (d, J = 1.1 Hz, IH), 7.85 (d, J = 6.9 Hz, IH), 7.71 - 7.61 (m, IH), 7.56 (m, IH), 7.50 - 7.35 (m, 2H), 6.92 (m, 2H), 3.98 (s, 3H), 2.70 - 2.49 (m, 2H), 1.92 (dd, J = 13.8, 7.4 Hz, 6H), 1.32 (d, J = 11.4 Hz, 6H). LCMS m/z 516.42 [M+H]0
201	As for compound 125 1 Λ° t N=\ / w° h N0X £0-0 -N 0 F	‘H NMR (400 MHz, Methanol-^) δ 8.48 (s, IH), 7.97 (d, J = LO Hz, IH), 7.80 (m, IH), 7.59 (qd, J = 6.4, 3.1 Hz, 2H), 7.49 7.37 (m, 2H), 7.01 (d, J = 1.1 Hz, IH), 6.94 (d, J = 1.2 Hz, IH), 4.02 (s, 3H), 2.75 - 2.52 (m, 2H), 1.98 (d, J = 13.7 Hz, 6H), 1.32 (m, 6H). LCMS m/z 516.33 [M+H]0
202	As for compound 125	JH NMR (400 MHz, Methanol-^) δ 8.01 (s, IH), 7.97 (m, IH), 7.77 (m, IH), 7.68 - 7.61 (m, IH), 7.60 - 7.53 (m, IH), 7.48

463

Compound	Method/Product	1H NMR; LCMS m/z [M+H]+
	z II G \ J u .... 0—-z to r 'Vll / x 11 / r O IZ f	- 7.38 (m, 2H), 6.96 - 6.88 (m, 2H), 3.96 (s, 3H), 2.70 - 2.50 (m, 2H), 1.91 (dd, J = 13.7, 7.2 Hz, 6H), 1.32 (d, J = 12.8 Hz, 6H). LCMS m/z 516.25 [M+H]+.

^T Prepared by Suzuki coupling from 3-[ -(2,2-dimethylpropanoyl)-5-(4-fluorυphenyl)-7iodo-pyrrolo[2,3-f]indazol-6-yl]-3-methyl-butanenitrile.

Tosyl protected intermediate. Methyl 5-(4-cyano-3,3-dimethyl-but-l-ynyl)thiophene-2carboxylate.

Compounds 203-254

Compounds 203-254 (Table 15) were prepared from compound 112 by amide coupling with the appropriate amine as described for the préparation of compound 128. In some examples, compounds are prepared by Suzuki coupling of the appropriate boronic acid with SH as 10 described for the préparation of compound 127. In some examples, compounds were prepared by

Larock indole formation according to the method described for compound 119.

Table 15. Method ofpréparation, structure, physicochemical data for compounds 203-254

Compound

203

204

Method/Product

As for Compound 127 from Sll

TI NMR,- LCMS m/z [M+H]⁺ ‘H NMR (400 MHz, DMSO4) δ 12.52 (s, IH), 8.87 (d, J = 6.7 Hz, IH), 8.00 (d, J = 7.8 Hz, 2H), 7.97 (s, 1 H), 7.71 (s, IH), 7.57 (m, 4H), 7.49 (t, J = 8.5 Hz, 2H), 6.88 - 6.78 (m, 2H), 4.66 (m, IH), 3.64 (dd, J = 10.0, 7.3 Hz, IH), 3.23 (dd, J = 10.1,4.6 Hz, IH), 3.06 (s, 2H), 3.02 (s, 3H), 2.59 (m, IH), 2.33 (dd, J = 16.8, 5.5 Hz, IH), 1.11 (s, 6H). LCMS m/z 540.4 [M+H]⁺. ’H NMR (400 MHz, Methanol-^) δ 7.91 (d, J = 1.0 Hz, IH), 7.88 (d, J = 0.7 Hz, IH), 7.68 (d, J = 0.7 Hz, IH), 7.52 - 7.44 (m, 2H), 7.40 - 7.29 (m, 2H), 7.09 (t, J= 1.1 Hz, IH), 6.84 (d, J = 1.2 Hz, IH), 5.76 - 5.62 (m, IH), 5.14 (m, 4H), 3.18 (s, 2H), 3.13 (s, 3H), 1.20 (s, 6H). LCMS m/z 460.3

464

Compound	Method/Product	‘H NMR; LCMS m/z [M+Hf
	r° H / aaa I vX AAA^N Aq Q ' F	[M+Hf.
205	As for Compound 128 from 112 O - O _-s- Vn °0NH O H / N~aAAx 1 x AT JA aaa^-n a0^ F	lH NMR (400 MHz, DMSOA) δ 13.84 (s, IH), 12.52 (s, IH), 8.32 (d, J = 7.9 Hz, 2H), 7.98 (s, IH), 7.69 (d, J = 7.9 Hz, 2H), 7.60 (m, 2H), 7.50 (m, 2H), 6.87 (t, J = 1.1 Hz, 1 H), 6.85 (d, J = 1.3 Hz, 1 H), 3.62 (s, 3H), 3.08 (s, 2H), 3.03 (s, 3H), 1.13 (s, 6H). LCMS m/z 619.28 [M+H]+.
206	As for Compound 128 from 112 H rV° hia J. O H / na+A. i +-AA-N Aq F	!H NMR (400 MHz, DMSOA,) δ 12.50 (s, IH), 8.62 (t, J = 5.6 Hz, IH), 8.04 (t, J = 5.7 Hz, IH), 7.98 (m, 3H), 7.58 (dd, J = 8.6, 5.0 Hz, 2H), 7.54 (d, J = 7.8 Hz, 2H), 7.49 (m, 2H), 6.83 (m, 2H), 3.26 (m, 2H), 3.06 (s, 2H), 3.02 (s, 3H), 1.85 (s, 3H), 1.11 (s, 6H). LCMS m/z 542.43 [M+Hf.
207	As for Compound 128 from 112	*H NMR (400 MHz, DMSO-î/6) δ 12.49 (s, IH), 8.72 (t, J = 6.1 Hz, IH), 7.99 (dm, 3H), 7.63 - 7.52 (m, 4H), 7.49 (dd, J = 9.9, 7.6 Hz, 2H), 6.89 6.76 (m, 2H), 4.57 (d, J = 6.3 Hz, IH), 4.44 (d, J = 6.3 Hz, IH), 3.63 (d, J = 6.1 Hz, IH), 3.12 - 2.97 (m, 6H), 1.11 (d, J = 3.6 Hz, 6H). Methylene from NH2CH2 overlaps with water LCMS m/z 543.38 [M+Hf.

465

Compound	Method/Product	'H NMR; LCMS m/z [M+111
	HO ov / VO Anh Cj H N-aA-A 1 U av F
208	As for Compound 128 from 112 0x NA ΑΝΠ n H / 1 / N J L / \ AA/A-N O F	‘H NMR (400 MHz, DMSO-J6) δ 12.47 (s, IH), 8.69 (t, J = 5.9 Hz, IH), 7.96 (s, IH), 7.93 (d, J = 7.8 Hz, 2H), 7.58 (m, 2H), 7.54 (d, J = 7.8 Hz, 2H), 7.48 (t, J = 8.5 Hz, 2H), 6.84 (d, .1 = 1.3 Hz, IH), 6.82 (d, J = 1.2 Hz, IH), 4.27 (dd, J = 9.0, 7.0 Hz, 2H), 3.67 (dd, J = 8.9, 7.1 Hz, 2H), 3.49 (m, 2H), 3.06 (s, 2H), 3.02 (s, 3H), 1.11 (s, 6H). 2H overlapping with water signal. LCMS m/z 570.42 [M+H]+.
209	As for Compound 128 from 112 VnA '? A /A 0 vJ H / n-AA-A 1 aXa ^AA^-N F	*H NMR (400 MHz, DMSO-4) δ 12.49 (s, IH), 7.97 (d, J = 1.1 Hz, IH), 7.65 (m 2H), 7.59 (m, 2H), 7.56 - 7.43 (m, 4H), 6.88 (m, IH), 6.83 (t, J = 1.2 Hz, IH), 4.07 (m, IH), 3.95 (m, 2H), 3.70 (m, 2H), 3.12 (s, 2H), 3.07 (s, 3H), 3.01 (s, 3H),2.37(m, 2H), 1.12 (s, 6H). LCMS m/z 589.39 [M+H]L
210	As for Compound 128 from 112	TH NMR (400 MHz, DMSO-^) δ 12.49 (s, 1 H), 7.97 (s, 1 H), 7.65 (d, J = 7.6 Hz, 2H), 7.58 (m, 2H), 7.54 - 7.43 (m, 4H), 6.88 (s, IH), 6.83 (s, IH), 4.03 (d, J = 4.3 Hz, IH), 3.97 (m, IH), 3.83 (dd, J =11.1, 3.8 Hz, IH), 3.74 (dd, J = 12.8, 4.4 Hz, IH), 3.07 (s, 2H), 3.01 (d,J = 4.2 Hz, 3H), 1.12 (s, 6H). 2H likely behinf the water peak. LCMS m/z 543.38 [M+H]+. |

466

Compound	Method/Product	'H NMR; LCMS m/z [M+H] '
	.OH + ^OH O H / n^-a^-A I ΆΑΑ N \— o \ F
211	As for Compound 128 from 112 Οχ H rt=\ ΝΆ Q v) H / x +A jaa 0' F	‘H NMR (40Ü MHz, DMSO4) δ 12.49 (s, IH), 8.51 (t, J = 5.6 Hz, IH), 8.02 - 7.96 (m, 2H), 7.95 (s, IH), 7.58 (m, 2H), 7.54 (d, J = 7.8 Hz, 2H), 7.49 (t, J = 8.5 Hz, 2H), 6.84 (d, J = 1.3 Hz, IH), 6.83 (d, J = 1.3 Hz, IH), 3.06 (s, 2H), 3.02 (d, J = 1.2 Hz, 3H), 2.25 (s, 3H), 1.11 (s, 6H). There 12H from methylenes that are likely behind the water and DMSO signais. LCMS m/z 583.47 [M+H]0
212	As for Compound 128 from 112 OH ov J-oh y NH O H ΝΛ JAAl 0 ' F	’H NMR (400 MHz, DMSO-<) δ 12.49 (s, IH), 8.50 (t, J = 5.7 Hz, IH), 8.04 - 7.92 (m, 3H), 7.58 (dd, J = 8.7, 4.9 Hz, 2H), 7.55 - 7.44 (m, 4H), 6.83 (dt, J = 5.1, 1.2 Hz, 2H), 3.69 (q, J = 5.7 Hz, IH), 3.45 (dd, J = 11.9, 6.5 Hz, 2H;overlaps with water), 3.26 (dt, J = 12.9, 6.1 Hz, 2H), 3.06 (s, 2H), 3.02 (d, J = 1.1 Hz, 3H), 1.11 (s, 6H). LCMS m/z 531.37 [M+H]0
213	As for Compound 128 from 112	lH NMR (400 MHz, DMSO-^) δ 12.49 (s, IH), 8.55 (t, J = 5.9 Hz, IH), 8.05 - 7.90 (m, 3H), 7.57 (m, 4H), 7.49 (t, J = 8.5 Hz, 2H), 6.84 (d, J = 1.2 Hz, IH), 6.82 (d, J = 1.2 Hz, IH), 3.89 3.74 (m, 3H), 3.71 (d, J = 9.0 Hz, 2H), 3.06 (s, 2H), 3.03 (d, J = 1.2 Hz, 3H), 2.01 (dt, J = 12.6, 8.6 Hz, IH), 1.87 1.73 (m, IH), LH (s, 6H).*1H overlaps with water. LCMS m/z 557.42

467

Compound	Method/Product	‘11 NMR; LCMS m/z [M+H]+
	HOX V 0 F-nh o H / nŒJff F	[M+H]4.
214	As for Compound 128 from 112 VH / F-x zo F zSf O 0 v H i Nv^VA L· nYXY F	‘H NMR (400 MHz, DMSO-rf6) δ 12.48 (s, IH), 8.81 (t, J = 5.5 Hz, JH), 7.98 (s, IH), 7.96 (m, 2H), 7.63 - 7.53 (in, 4H), 7.49 (t, J = 8.5 Hz, 2H), 6.87 6.77 (m, 2H), 3.77 (q, J = 6.6 Hz, 2H), 3.48 (t, J = 7.0 Hz, 2H), 3.06 (s, 2H), 3.02 (s, 3H), 2.85 (p, J = 6.4 Hz, 1 H), 1.11 (s, 6H), 1.05 (m, 4H). LCMS m/z 589.39 [M+HÊ
215	As for Compound 128 from 112 CR 4 N—\ VNH 7 ) F 0' n F\ H VJ H N J £ ;V F	lH NMR (400 MHz, DMSO-rf6) δ 12.48 (s, I H), 8.64 (t, J = 5.7 Hz, 1 H), 8.04 - 7.85 (m, 3H), 7.58 (m, 2H), 7.53 (d, J = 7.9 Hz, 2H), 7.49 (t, J = 8.5 Hz, 2H), 6.84 (s, JH), 6.83 (s, IH), 3.47 (m, 4H), 3.31 - 3.23 (m, 4H), 3.06 (s, 2H), 3.02 (s, 3H), 1.11 (s, 6H). LCMS m/z 569.47 [M+H]4.
216	As for Compound 128 from 112	'H NMR (400 MHz, DMSO-ri6) δ 12.51 (s, IH), 8.96 (d, J = 7.3 Hz, IH), 8.00 (d, J = 7.8 Hz, 2H), 7.97 (s, 1 H), 7.58 (m, 2H), 7.54 (d, J = 7.8 Hz, 2H), 7.49 (t, J = 8.5 Hz, 2H), 6.83 (m, 2H), 4.49 (p, J = 8.2 Hz, IH), 3.79 (p, J = 8.8 Hz, IH), 3.06 (s, 2H), 3.02 (s, 3H), 2.93 (s, 3H), 2.64 - 2.57 (m, 2H), 2.49 2.41 (m, 2H), 1.11 (s, 6H). LCMS m/z 589.34 [M+H]4.

468

Compound	Method/Product	'H NMR; LCMS m/z [M+H]+
	H 0 AT Cr - Anh Cx H / I ^'ΑΑ'-Ν V-Q F
217	As for Compound 128 from 112 0 \\ / 7 o °y-NH Ça H / m ÏA ^-AA^n F	‘H NMR (400 MHz, DMSO-A) δ 12.52 (s, IH), 8.69 (t, J = 5.7 Hz, IH), 8.04 - 7.91 (m, 3H), 7.58 (m, 2H), 7.54 (d, J = 7.6 Hz, 2H), 7.49 (t, J = 8.5 Hz, 2H), 6.84 (s, IH), 6.83 (s, IH), 3.23 (dd, J = 9.8, 6.1 Hz, 2H), 3.06 (s, 2H), 3.02 (m, 6H), 2.01 (p, J = 6.9 Hz, 2H), 1.11 (s, 6H). 2H from CH2 behind the water peak. LCMS m/z 577.38 [M+H]+.
218	As for Compound 127 from SU o nX, f N H / .γνΑ O A Al ' N x~ O F	lH NMR (400 MHz, Methanol-^) δ 8.62 (s, 2H), 7.94 (d, J = 1.0 Hz, IH), 7.59 - 7.46 (m, 2H), 7.44 - 7.28 (m, 2H), 7.00 (t, J = 1.1 Hz, IH), 6.88 (d, J = 1.1 Hz, IH), 4.11 (s, 3H), 3.13 (s, 3H), 3.12 (s, 2H), 1.16 (s, 6H). LCMS m/z 446.26

469

Compound	Method/Product	lH NMR; LCMS m/z fM+H]+
219	As for Compound 127 from SU Cr / f ° Vn H nja F	‘h NMR (400 MHz, Methanol-^) δ S.09 (s, IH), 7.91 (d, J = L1 Hz, IH), 7.83 (d, J = 0.7 Hz, IH), 7.62 (d, J = 0.7 Hz, IH), 7.53 - 7.44 (m, 2H), 7.39 7.29 (m, 2H), 7.10 (t, J = 1.1 Hz, IH), 6.83 (d, J = 1.1 Hz, IH), 4.77 (dd, J = 6.9, 5.9 Hz, 2H), 3.81 (t, J = 6.3 Hz, 2H), 3.19 (s, 2H), 3.15 (s, 3H), 2.91 (m, 3H), 1.20 (s, 6H). LCMS m/z 510.28 [M+H]+.
220	As for Compound 127 from SU O m X OH V p H / \T JW F	'H NMR (400 MHz, Methanol-^) Ô 7.91 (d, J = 1.1 Hz, IH), 7.88 (d, J = 0.7 Hz, IH), 7.58 (d, J = 0.7 Hz, IH), 7.51 - 7.43 (m, 2H), 7.39 - 7.28 (m, 2H), 7.14 (t, J = LI Hz, IH), 6.84 (d, J = 1.1 Hz, IH), 3.21 (s, 2H), 3.13 (s, 3H), 1.94 (s, 6H), 1.20 (s, 6H). LCMS m/z 490.33 [M+H]+.
221	As for Compound 127 from SU OH H / ,nvv4 I Nu J/Ay F	’H NMR (400 MHz, Methanol-^) δ 7.90 (d, J = L1 Hz, IH), 7.74 (d, J = 0.8 Hz, IH), 7.57 (d, J = 0.7 Hz, IH), 7.50 - 7.43 (m, 2H), 7.38 - 7.29 (m, 2H), 7.14 (t, J = 1.1 Hz, IH), 6.83 (d, J = 1.1 Hz, IH), 4.35 (t, J = 5.5 Hz, 2H), 3.99 (t, J = 5.5 Hz, 2H), 3.19 (s, 2H), 3.13 (s,3H), 1.20 (s, 6H). LCMS m/z 448.29 [M+H]*.
222	As for Compound 127 from SU O M Ί Ri '< VP 0 H / NW0\ F	1H NMR (400 MHz, Methanol-^) δ 7.92 (d, J = 0.7 Hz, IH), 7.91 (d, J = 1.1 Hz, IH), 7.72 (d, J = 0.7 Hz, IH), 7.56 - 7.42 (m, 2H), 7.35 (m, 2H), 7.12 (t, J = 1.1 Hz, IH), 6.85 (d, J = 1.2 Hz, IH), 5.71 (d, J = 0.8 Hz, 2H), 3.20 (s, 2H), 3.15 (s, 3H), 3.06 (d, J = 0.8 Hz, 3H), 1.21 (s, 6H). LCMS m/z 496.29 [M+H]+.
223	As for Compound 127 from SU	'H NMR (400 MHz, Methanol-δ 8.01 (d, J_= 1.1 Hz, IH), 7.93 (d, J =

470

Compound	Method/Product	‘H NMR; LCMS m/z [M+Hf
	AON /'N H / navX I A XA άΑή a0^ F	0.7 Hz, IH), 7.69 (d, J = 0.7 Hz, IH), 7.63-7.51 (m, 2H), 7.51 - 7.36 (m, 2H), 7.25 (t, J = 1.1 Hz, IH), 6.94 (d, J = 1.1 Hz, IH), 3.96 (s, 2H), 3.30 (s, 2H), 3.24 (s, 3H), 1.76 (s, 6H), 1.30 (s, 6H). LCMS m/z 476.33 [M+H]+.
224	As for Compound 127 from SU M ViOf \A o H / aaA i AXXAA ^^AA-’N Aq F	’H NMR (400 MHz, Methanol-δ 7.90 (d, J = 1.1 Hz, IH), 7.74 (s, IH), 7.55 (s, IH), 7.52 - 7.44 (m, 2H), 7.34 (m, 2H), 7.22 (t, J = 1.1 Hz, IH), 6.83 (d, J = 1.1 Hz, IH), 4.97 (s, 2H), 3.22 (s, 2H), 3.14 (s, 3H), 1.21 (s, 6H). LCMS m/z 462.24 [M+Hf.
225	As for Compound 128 from 112 O 0 /A-S^ yNA b O H / ,naAa\ L· A X Xa a'a^n a0^ F	‘H NMR (400 MHz, DMSO-rff>) δ 12.48 (s, IH), 7.97 (d, J = 1.4 Hz, IH), 7.81 (d, J = 7.7 Hz, 2H), 7.64 - 7.53 (m, 4H), 7.49 (t, J = 8.5 Hz, 2H), 6.87 (d, J = 1.2 Hz, IH), 6.83 (s, IH), 4.78 (m, IH), 4.58 (m, IH), 4.36 (m, 3H), 3.11 (s, 3H), 3.06 (s,2H), 3.01 (s, 3H), 1.12 (s, 6H). LCMS m/z 575.26 [M+Hf.
226	As for Compound 128 from 112 μ 0 H - AV'SX h„._J 'o °yNH 0 H / ν-^αΑ^ 1 XX XaX. aaa^n a0 F	‘H NMR (400 MHz, DMSO-î/6) δ 12.50 (s, IH), 8.89 (d, J = 7.4 Hz, IH), 8.04 - 7.91 (m, 3H), 7.63 - 7.52 (m, 4H), 7.49 (t, J = 8.5 Hz, 2H), 6.83 (m, 2H), 4.66 (p, J = 7.9 Hz, IH), 3.98 3.78 (m, IH), 3.06 (s, 2H), 3.02 (s, 3H), 2.99 (s, 3H), 2.79 - 2.68 (m, 2H), 2.61 (m,2H), 1.10 (s, 6H). LCMS m/z 589.35 [M+Hf.

471

Compound	Method/Product	‘H NMR; LCMS m/z [M+H]+
227	As for Compound 128 from 112 X^-NH O H / <T JAv F	'H NMR (400 MHz, DMSO-J6) δ 12.49 (s, IH), 8.83 (t, J = 5.7 Hz, IH), 8.01 - 7.93 (m, 3H), 7.62 - 7.53 (m, 4H), 7.49 (t, J = 8.5 Hz, 2H), 6.87 6.80 (m, 2H), 3.75 (q, J = 6.5 Hz, 2H), 3.44 (t, J = 6.9 Hz, 2H), 3.09 (s, 3H), 3.06 (s, 2H), 3.02 (s, 3H), 1.11 (s, 6H). LCMS m/z 563.29 [M+H]+.
228	As for Compound 128 from 112 VA O H / + T JJv v \ (V F	’H NMR (400 MHz, DMSO-^) δ 12.48 (s, IH), 8.71 (i, J = 5.4 Hz, IH), 8.57 (s, IH), 8.02 (d, J = 1.2 Hz, IH), 7.96 (d, J = 1.3 Hz, 1FI), 7.92 (d, J = 7.8 Hz, 2H), 7.58 (m, 2H), 7.54 (d, J = 7.9 Hz, 2H), 7.49 (t, J = 8.5 Hz, 2H), 6.83 (m, 2H), 4.43 (t, J = 6.0 Hz, 2H), 3.72 (q, J = 5.9 Hz, 2H), 3.06 (s, 2H), 3.02 (m, 3H), 1.11 (s, 6H). LCMS m/z 552.27 [M+H].
229	As for Compound 128 from 112 ^OH f \ OH X-nh o H / XJ X / \ F	'H NMR (400 MHz, DMSO-î76) δ 12.50 (s, IH), 8.45 (t, J = 6.1 Hz, IH), 8.00 (d, J = 7.8 Hz, 2H), 7.97 (d, J = 1.3 Hz, IH), 7.59 (m, 2H), 7.55 (d, J = 7.6 Hz, 2H), 7.49 (t, J = 8.5 Hz, 2H), 6.85 (s, IH), 6.83 (s, IH), 4.76 (s, IH), 4.65 (s, IH), 3.42 m, 2H), 3.28 (m. 2H), 3.07 (s, 2H), 3.03 (s, 3H), 1.11 (m, 9H). LCMS m/z 545.34 [M+H]+.
230	As for Compound 127 from Sll	lH NMR (400 MHz, Methanol-J4) δ 7.90 (d, J = 1.1 Hz, IH), 7.74 (d, J = 0.8 Hz, IH), 7.56 (d, J = 0.8 Hz, IH), 7.51 - 7.43 (m, 2H), 7.38 - 7.29 (m, 2H), 7.13 (t, J = 1.1 Hz, IH), 6.83 (d, J = 1.1 Hz, 1H),4.42 (dd, J = 14.0,4.6 Hz, IH), 4.26 (dd, J = 14.0, 7.2 Hz, IH), 4.09 (dq, J = 7.2, 5.1 Hz, IH),

472

Compound	Method/Product	‘H NMR; LCMS m/z [M+Hf
	OH \X ^OH H / X - v F	3.65 - 3.48 (m, 2H), 3.20 (s, 2H), 3.14 (s, 3H), 1.20 (s, 6H). LCMS m/z 478.29 [M+H]X
231	As for Compound 127 from SU A N^\ A H / < J A < \ / F	‘H NMR (400 MHz, Methanol-A) δ 8.87 (dd, J = 2.1, 0.9 Ηζ,ΙΗ), 8.15 (ddd, J = 7.8, 5.3, 0.9 Hz, IH), 8.09 (ddd, J = 7.8, 3.6, 2.0 Hz, IH), 7.94 (d, J = 1.0 Hz, IH), 7.61 - 7.48 (m, 2H), 7.44 - 7.33 (m, 2H), 6.93 (t, J = 1.1 Hz, IH), 6.89 (d, J = 1.2 Hz, IH), 3.10 (s, 2H), 3.10(s, 3H), 1.90 (m, 6H), 1.15 (s, 6H). LCMS m/z 491.32 [M+H]+.
232	As for Compound 127 from SU CfepL o H / <ji J A / F	‘H NMR (400 MHz, Methanol-A) δ 7.94 (d, J = 1.1 Hz, IH), 7.93 - 7.87 (m, 2H), 7.70 - 7.65 (m, 2H), 7.56 7.50 (m, 2H), 7.37 (m, 2H), 6.92 (t, J = 1.1 Hz, IH), 6.87 (d, J = Li Hz, IH), 3.10 (s, 2H), 3.09 (s, 3H), 1.90 (s, 3H), 1.87 (s, 3H), 1.16 (s, 6H). LCMS m/z 490.33 [M+H]X
233	As for Compound 128 from 112 O. H y-N ( NH y i ^A H / ° NAAA I ATA X—o X ' F	fH NMR (400 MHz, DMSO-A) δ 12.51 (s, IH), 8.54 (d, J = 7.3 Hz, IH), 8.02 - 7.92 (m, 3H), 7.62 - 7.52 (m, 4H), 7.53 - 7.44 (m, 3H), 6.83 (m, 2H), 4.23 (s, IH), 3.19 (m, IH), 3.07 (s, 2H), 3.03 (s, 3H), 2.41 - 2.27 (m, 2H), 1.95 (m, 2H), 1.11 (s, 6H). One CH likely overlaps with the water peak LCMS m/z 554.44 [M+H]X
234	As for Compound 128 from 112	lH NMR (400 MHz, DMSO-A) δ 12.50 (s, IH), 8.75 (d, J = 8.4 Hz, IH), 8.00 (d, J = 7.9 Hz, 2H), 7.95 (d, J =

473

Compound	Method/Product	’H NMR; LCMS m/z [M+H] +
	H _ N-A^OH ° \ J Οχ y-NH O H / N VV4 I Ai TAU AAn A U ' F	10.8 Hz, 2H), 7.62 - 7.52 (m, 4H), 7.49 (t, J = 8.7 Hz, 2H), 6.85 (s, IH), 6.83 (s, IH), 4.99 (br s, IH), 4.72 (q, J = 9.3 Hz, IH), 3.57 (m, IH), 3.43 (m, 2H), 3.06 (s, 2H), 3.03 (s, 3H), 2.27 (t, J = 10.9 Hz, IH), 2.22 - 2.09 (m, IH), 1.11 (s, 6H). LCMS m/z 570.46 [M+H]+.
235	As for Compound 128 from 112 X NH 0 H-XX y-NH 0 O H / AAA 1 A tau α-ΑΑ^ν Ao O ' F	*H NMR (400 MHz, DMSOA) δ 12.49 (s, 1 H), 8.78 (d, J = 8.4 Hz, IH), 8.01 (d, J = 7.9 Hz, 2H), 7.96 (s, IH), 7.89 (s, IH), 7.63 - 7.53 (m, 4H), 7.49 (t, J = 8.6 Hz, 2H), 6.85 (s, IH), 6.83 (s, IH), 4.63 (q, J = 9.2 Hz, 1 H), 3.27 (m, 2H), 3.07 (s, 2H), 3.03 (s, 3H), 2.39 (m, IH), 2.08 (p, J = 9.6 Hz, IH), 1.12 (s, 6H). LCMS m/z 540.4 [M+H]+.
236	As for Compound 128 from 112 H N ox y-NH O H / N—AA 1 ACtAU O F	lH NMR (400 MHz, DMSOA) δ 12.50 (s, IH), 8.56 (d, J = 7.2 Hz, IH), 8.03 - 7.95 (m, 3H), 7.66 - 7.52 (m, 5H), 7.49 (t, J = 8.6 Hz, 2H), 6.83 (m, 2H), 4.26 (m, IH), 3.23 (m, 2H), 3.07 (s, 2H), 3.03 (s, 3H), 2.40 - 2.24 (m, 2H), 2.00 (m, IH), 1.77 (m, IH), 1.11 (s, 6H). LCMS m/z 554.44 [M+H]+.
237	As for Compound 128 from 112	Ή NMR (400 MHz, DMSOA) δ 12.48 (s, IH), 8.72 (d, J = 8.3 Hz, IH), 8.00 (d, J = 7.9 Hz, 2H), 7.96 (s, 1 H), 7.68 (s, IH), 7.59 (m, 2H), 7.55 (d, J = 7.9 Hz, 2H), 7.49 (t, J = 8.5 Hz, 2H), 6.85 (s, IH), 6.83 (s, IH), 4.43 (m,

474

Compound	Method/Product	*H NMR; LCMS m/z [M+H]+
	NH Ο. / Ό Anh O H / N-aAA I A Cm F	IH), 3.27 - 3.16 (m, 2H), 3.07 (s, 2H), 3.03 (s, 3H), 2.06 (m, IH), 1.87 (m, 3H), 1.12 (s, 6H). LCMS m/z 554.39 [M+H]+.
238	As for Compound 128 from 112 0 ' y—NH H-MH Ov ~ \ ANH ' ÇJ H / n-aaa 1 naI AV 8—O F	’H NMR (400 MHz, DMS(A6) δ 12.51 (s, IH), 9.20 (d, J = 8.3 Hz, IH), 8.24 (s, IH), 8.01 (d, J = 7.9 Hz, 2H), 7.97 (s, IH), 7.58 (m, 4H), 7.49 (t, J = 8.5 Hz, 2H), 6.84 (s, 1 H), 6.83 (s, IH), 4.60 (dd, J = 8.4, 2.3 Hz, IH), 3.74 (m, IH), 3.06 (s, 2H), 3.02 (s, 3H), 1.35 (d, J = 6.1 Hz, 3H), 1.11 (s, 6H). LCMS m/z 540.44 [M+H]fl
239	As for Compound 128 from 112 HO _ j/^OH VO O H / NaAA 1 NU JW 8-AAa 8—0 fl ' F	lH NMR (400 MHz, DMSO-t/6) δ 12.48 (s, IH), 7.96 (s, IH), 7.59 (m, 2H), 7.49 (m, 6H), 6.89 (s, IH), 6.83 (s, IH), 4.70 (m, IH), 4.46 (m, IH), 4.06 (m, IH), 3.30 - 3.11 (m, 3H), 3.07 (s, 2H), 3.00 (s, 3H), 1.93 - 1.64 (m, 2H), 1.53 (m, 2H), 1.12 (s, 6H). LCMS m/z 571.41 [M+H]+.

475

Compound	Method/Product	lH NMR; LCMS m/z [M+Hf
2401	As for Compound 128 from 112 Οχ F /0H 0H M H / I nU1F Q ' F	‘H NMR (400 MHz, DMSOF) δ 12.47 (s, IH), 7.96 (s, IH), 7.64 (m, 2H), 7.58 (m, 2H), 7.54 - 7.42 (m, 4H), 6.87 (s, IH), 6.82 (s, IH), 5.01 - 4.82 (m, 2H), 3.66 (m, 3H), 3.51 - 3.41 (m, IH), 3.29 (m, IH), 3.06 (s, 2H), 3.01 (s, 3H), 2.02 (m, IH), 1.74 (m, IH), 1.12 (s, 6H). LCMS m/z 557.42 [M+H]+.
241	As for Compound 128 from 112 P~0 O H / n^+F, i àa Fl FF ^0 O F	’H NMR (400 MHz, DMSO-A) δ 12.47 (s, IH), 7.96 (s, IH), 7.63 - 7.39 (m, 8H), 6.87 (s, IH), 6.82 (s, IH), 3.84 (m, 2H), 3.55 (t, J = 7.1 Hz, 2H), 3.11 (s, 2H), 3.06 (s, 5H), 3.01 (s, 3H), 2.91 (m, 1 H), 1.11 (s, 6H). NMR shows conformers. LCMS m/z 577.42 [M+H]4.
242	As for Compound 128 from 112 H F Fo ox * v-nh o H / N-^xF. 1 F	’H NMR (400 MHz, DMSO-ri6) Ô 12.50 (s, IH), 9.20 (d, J = 8.5 Hz, IH), 8.09 (s, IH), 8.01 (d, J = 7.9 Hz, 2H), 7.97 (s, IH), 7.58 (m, 4H), 7.49 (t, J = 8.6 Hz, 2H), 6.85 (s, IH), 6.83 (s, IH), 5.12(m, 1H),3.52 (t,J = 5.4Hz, IH), 3.06 (s, 2H), 3.02 (s, 3H), 1.11 (s, 6H). There is likely a C-H behind the water peak. LCMS m/z 526.4 [M+H]4.
243	As for Compound 128 from 112	F NMR (400 MHz, DMSO-t/6) δ 12.48 (s, IH), 8.21 (s, IH), 7.97 (s, 1 H), 7.64 - 7.56 (m, 4H), 7.54 (d, J = 7.9 Hz, 2H), 7.49 (t, J = 8.6 Hz, 2H), 6.89 (s, IH), 6.83 (s, IH), 4.09 (m, 2H), 3.74 (m, 2H), 3.07 (s, 2H), 3.02 (s, 3H), 1.12 (s, 6H). A CH2 multiplet

476

Compound	Method/Product	’H NMR; LCMS m/z fM+H]+
	0 vôH o H / i nUL V A N A F	is likely behind the water peak. LCMS m/z 54Û.44 [M+H]+.
244	As for Compound 128 from 112 H N > OH 0 \ J °VNH 0 H / N^A^A 1 VX X/v AAA^N Aq 0 ' F	*H NMR (400 MHz, DMSO-î/6) δ 12.49 (s, IH), 8.77 (d, J = 8.4 Hz, IH), 8.01 (d, J = 7.9 Hz, 2H), 7.96 (s, IH), 7.93 (s, IH), 7.64 - 7.53 (m, 4H), 7.49 (t, J = 8.6 Hz, 2H), 6.85 (s, IH), 6.83 (s, IH), 4.90 (t, J = 5.4 Hz, IH), 4.69 (q, J = 9.3 Hz, IH), 3.59 (m, IH), 3.45 (m, 2H), 3.06 (s, 2H), 3.02 (s, 3H), 2.47 - 2.37 (m, IH), 1.75 (q, J = 10.4 Hz, 1 H), 1.12 (s, 6H). LCMS m/z 570.51 [M+Hf.
245	As for Compound 128 from 112 0, d Anv_ /A < AO k i N v H naVÀ L· n J TVj AAA^N Aq A F	lH NMR (400 MHz, Methanol-e//) Ô 8.01 - 7.94 (m, 2H), 7.92 (d, J = 1.1 Hz, IH), 7.61 - 7.55 (m, 2H), 7.55 7.49 (m, 2H), 7.37 (m, 2H), 6.92 (t, J = 1.2 Hz, IH), 6.86 (d, J= 1.2 Hz, IH), 4.85 -4.80 (m, 1 H), 3.85 (dd, J= 10.5, 7.4 Hz, IH), 3.42 (dd, J = 10.5, 4.5 Hz, 1 H), 3.10 (s, 2H), 3.09 (s, 3H), 2.80 (dd, J = 17.3, 8.6 Hz, IH), 2.50 (dd, J = 17.3, 5.5 Hz, IH), 1.16 (s, 6H). LCMS m/z 540.34 [M+H]+.
246	As for Compound 128 from 112	Xi NMR (400 MHz, Methanol-d4) δ 8.01 - 7.94 (m, 2H), 7.94 - 7.89 (m, IH), 7.62 - 7.55 (m, 2H), 7.55 - 7.48 (m, 2H), 7.42 - 7.32 (m, 2H), 6.92 (m, IH), 6.86 (d, J = 1.1 Hz, IH), 4.85 4.79 (m, IH), 3.85 (dd, J = 10.5, 7.3 Hz, IH), 3.42 (dd, J = 10.5, 4.6 Hz, _1H), 3.10 (s, 2H), 3.09 (s, 3H), 2.80

477

Compound	M ethod/Prod uct	‘il NMR; LCMS m/z [M+Hf
	o. L! 3 y H Γ ° NvVA A A J X/ \ άαν o F	(dd, J = 17.2, 8.6 Hz, IH), 2.50 (dd, J = 17.2, 5.5 Hz, IH), 1.16 (s, 6H). LCMS m/z 540.39 [M+Hf.
247	As for Compound 127 from SU N JXnh2 /AN J \A o AXA. x-'-AA'-N =0 F	!H NMR (400 MHz, DMSO-rf6) δ 12.53 (s, IH), 7.94 (s, IH), 7.91 (s, IH), 7.58 (s, IH), 7.56 - 7.41 (m, 4H), 7.31 (s, IH), 7.07 (d, J = 1.2 Hz, I H), 6.84 (s, IH), 6.78 (d, J = 1-1 Hz, IH), 3.14 (s, 2H), 3.05 (s, 3H), 1.81 (s, 6H), 1.13 (s, 6H). LCMS m/z 489.42 [M+Hf.
248	As for Compound 127 from SU o, Anh2 nX^ 'ojj/ H / NxAj 1 N J £ y—A F	'H NMR (400 MHz, DMSOA) δ 12.49 (s, IH), 8.18 - 8.07 (m, IH), 7.97 (s, IH), 7.87 (d, J = 7.4 Hz, IH), 7.78 (d, J = 7.4 Hz, IH), 7.73 (s, IH), 7.65 (m, IH), 7.57 - 7.43 (m, 3H), 6.82 (s, IH), 6.77 (s, IH), 3.95 (s, 3H), 3.05 3.00 (m, 2H), 2.98 (s, 3H), 1.10 (s, 6H). LCMS m/z 488.38 [M+Hf.
249	As for Compound 127from SU oAH zTn H / NvvA a a J τνχ +AAN x— F	‘H NMR (400 MHz, MethanolA) δ 8.12 (d, J= 1.1 Hz, IH), 7.59-7.52 (m, 2H), 7.51 - 7.43 (m, IH), 7.36 (m, 2H), 7.08 (m, IH), 6.93 (m, 1.1 Hz, IH), 5.05 (s, 2H), 3.20 (m, 2H), 3.13 (m, 3H), 2.14 (s, 3H), 1.20 (m, 6H). LCMS m/z 476.41 [M+Hf.
250	As for Compound 127from SU	Ai NMR (400 MHz, Methanol A) δ 8.11 (s, 1 H), 7.83 (s, IH), 7.57 (m, IH), 7.48 - 7.41 (m, IH), 7.41 - 7.31 (m, 2H), 7.07 (t, J = 1.1 Hz, IH), 6.92

478

Compound	Method/Product	*H NMR; LCMSm/z [M+H]+
	Z Λ Γ T v ' -πΆΑ 1_ z o oA^ o z	(s, IH), 3.24 (d, J = 9.0 Hz, IH), 3.15 (d, J = 9.0 Hz, IH), 3.13 (s, 3H), 2.13 (s, 3H), 1.92 (d, J = 7.0 Hz, 6H), 1.20 (d, J = 11.5 Hz, 6H). LCMS m/z 504.41 [M+H]+.
251	As for Compound 127from SU O \ u n-A^oh NJ H / ΑΆ4 1 nv(Ja\ Y-'AA^'N ^0 F	'H NMR (400 MHz, Methanol A) δ 8.12 (d, J = 1.1 Hz, IH), 7.55 - 7.47 (m, 2H), 7.41 - 7.31 (m, 2H), 7.20 (t, J = 1.2 Hz, 1 H), 7.00 (s, 1 H), 6.94 (d, J = 1.1 Hz, 1 H), 4.27 (s, 3H), 3.19 (s, 2H), 3.11 (s, 3H), 1.21 (s, 6H). LCMS m/z 462.37 [M+H]+.
252	As for Compound 127from SU HO AAo v—S H A N->A\A i <T EAr N =0 0 ' F	’H NMR (400 MHz, MethanolA) δ 7.93 (d, J = 1.0 Hz, 1 H), 7.84 (d, J = 3.7 Hz, IH), 7.56 - 7.48 (m, 2H), 7.42 7.32 (m, 2H), 7.16 - 7.11 (m, 2H), 6.87 (d, J = 1.1 Hz, IH), 3.18 (s, 2H), 3.14 (s, 3H), 1.24 (s, 6H). LCMS m/z 464.32 [M+H]\
253	As for Compound 128 from 119 °ANH2 O n^aA ^oh âX XV-a F	'H NMR (400 MHz, Methanol-A) δ 8.04 - 7.96 (m, 2H), 7,92 (d, J = L1 Hz, IH), 7.63 - 7.58 (m, 2H), 7.59 7.54 (m, 2H), 7.39 - 7.31 (m, 2H), 6.92 (t, J = 1.1 Hz, IH), 6.85 (d, J= 1.2 Hz, IH), 3.45 (s,2H), 1.11 (s, 6H). LCMS m/z 443.36 [M+H]L

479

Compound	Method/Product	'H NMR; LCMS m/z [M+H]+
254	Larock method as for compound 119 / Ao V/ H f^ 1 ΝχΧΧΑ<· OH θ F	lH NMR (400 MHz, Methanol-eL) δ 8.67 (s, IH), 7.91 (s, IH), 7.86 (s, IH), 7.58 (m, 2H), 7.37 (t, J = 8.6 Hz, 2H), 6.92 (s, IH), 6.88 (s, IH), 3.44 (s, 2H), 2.79 (s, 3H), 2.03 - 1.88 (m, 6H), 1.10 (s, 6H). LCMS m/z 491.23 [M+H]+.

l. Protected boronic acid

Compound 255

4-[6-(l,I-dimethyl-2-methylsulfonyl-ethyl)-5-(4-fluorophenyl)-lH-pyrrolo[2,3-f] indazol-7yl]benzoic acid (255)

Compound 255-258 (Table 16) were prepared from C190 and C191 by Larock indole 10 cyclization, followed by removal of the N-tosyl group and methyl ester by hydrolysis as described for compound 125.

IH NMR (400 MHz, Methanol-d4) δ 8.1 S - 8.10 (m, 2H), 7.93 (d, J = 1.1 Hz, JH), 7.71 7.66 (m, 2H), 7.66 - 7.63 (m, 2H), 7.41 (m, 2H), 6.92 (t, J = 1.1 Hz, IH), 6.84 (d, J = 1.2 Hz, ÏH), 3.39 (s, 2H), 2.81 (s, 3H), 1.40 (s, 6H). LCMS m/z 506.31 [M+H]⁺.

Compounds 256-258

Table 16. Method ofpréparation, structure, physicochemical data for compounds 256-258

480

Compound	Structure	Method	!H NMR; LCMS m/z [M+H]+
256	H rX	i AA	Οχ Α-νη2 >—fl O s— II w ° F	As for compound 255	'H NMR (400 MHz, DMSO-(4) δ 12.51 (s, IH), 8.09 (s, IH), 8.01 (d, J = 7.9 Hz, 2H), 7.97 (s, 1 H), 7.69 (dd, J = 8.7, 5.0 Hz, 2H), 7.61 - 7.50 (m, 4H), 7.46 (s, IH), 6.SI (s, IH), 6.80 (s, 1 H), 2.86 (s,3H), 1.32 (s, 6H). CH2 overlapps with water peak LCMS m/z 505.36 [M+H]+.
257	H N·^ V	N' Ao	O u P-^ J A F	O II -s— II o	As for compound 255	‘HNMR (400 MHz, Methanol-d#) δ 8.93 (t, J = L5 Hz, IH), 8.208.09 (m, 2H), 7.95 (d, J = 1.1 Hz, IH), 7.767.66 (m, 2H), 7.49 7.37 (m, 2H), 6.90 (t, J = 1.1 Hz, IH), 6.87 (d, J = 1.1 Hz, IH), 3.38 (s, 2H), 2.84 (s, 3H), 1.91 (dd, J= 13.7, 6.9 Hz, 6H), 1.38 (s, 6H). LCMS m/z 539.4 [M+H].
258	H <ζ	N' // Ja	O u P-^ V F	o II -S~ II o	As for compound 255	‘HNMR (400 MHz, Methanol-iZ?) δ 8.76 8.63 (m, IH), 7.94 (d, J= 1.1 Hz, IH), 7.90 (m, IH), 7.70 (m, 2H), 7.43 (m, 2H), 6.90 (t, J = 1.1 Hz, IH), 6.86 (d. J = 1.1 Hz, IH), 3.38 (d, J = 1.8 Hz, 2H), 2.84 (s, 3H), 2.78 (br s, 3H), 1.94 (dd, J = 13.5, 7.8 Hz, 6H), 1.38 (s, 6H). LCMS m/z 553.18 [M+H]+.

4SI

Compound 259

A-[5-(4-fluorophenyl)-6-(l-hydroxy-2-methoxy-l-methyl-ethyl)-lH-pyrrolo[2,3-f] indazol- 7yl] benzoic acid (259)

Compound 259 was prepared from C190 and methyl 4-(3-hydroxy-4-methoxy-3-methylbut-l-ynyl)benzoate using the method described for the préparation of compound 255.

Compounds 260-277

Compounds 260-277 (Table 17) were prepared from Cl and the appropriate alkyne using 10 the routes described for compounds 107-111. In some examples, compounds were prepared from C117orC190 using the Larock indole method as described for compound 125.

'H NMR (300 MHz, DMSO-rf₆) δ 12.52 (s, IH), 8.00 - 7.89 (m, 3H), 7.60 - 7.45 (m, 2H), 7.45 7.30 (m, 4H), 6.97 (t, J = 1.1 Hz, IH), 6.86 (d, J = 1.0 Hz, IH), 4.95 (s, IH), 3.22 (d, J = 3.2 Hz, 2H), 3.03 (s, 3H), 1.26 (s, 3H). LCMS m/z 460.34 [M+Hf.

482

Table 17. Method ofpréparation, structure, physicochemical data for compounds 260-277

Compound	Structure	Method	‘H NMR;1CMS/h/z [M+H]+
260	O H / / A X X αΥλ Α,Αν AO F	Suzuki Method. As for compounds 107-111.	‘H NMR (400 MHz, Methanol A) δ 7.98 (d, J = 1.1 Hz, IH), 7.97-7.89 (m, 2H), 7.68 (dd, J = 8.2, 2.6 Hz, 2H), 7.55 - 7.47 (m, 2H), 7.42 - 7.32 (m, 3H), 7.05 (d, J = l.l Hz, IH), 4.72 (d, J = 5.9 Hz, 2H), 3.92 -3.82 (m, 2H), 2.19 (q, J = 7.4 Hz, 2H), 1.89 (s, 3H), 1.86 (s, 3H), 1.18 (t, J = 7.5 Hz, 3H). LCMS m/z 488.34 [M+H]+.
261	A f ° 0=\ o ΞΕ	Suzuki Method. As for compounds 107-111.	lH NMR (400 MHz, Methanol A) δ 7.96 (d, J = 1.0 Hz, IH), 7.80 (d, J = 0.8 Hz, IH), 7.65 (d, J = 0.8 Hz, IH), 7.52-7.44 (ni, 2H), 7.43 (m, IH), 7.39-7.31 (m, 2H), 7.03 (d,J=1.2 Hz, IH), 5.08 (s, 2H), 4.86 (m,2H), 3.93 (d, J = 5.9 Hz, 2H), 2.15 (q, J = 7.4 Hz, 2H), 1.13 (t, J = 7.4 Hz, 3H). LCMS m/z 460.34 [M+H]+.
262	O h°X An A naaA \ NXX XaV F	Suzuki Method. As for compounds 107-111.	*H NMR (40Ü MHz, Methanol A) δ 7.96 (d, J =1.1 Hz, IH), 7.88 (d, J = 0.8 Hz, IH), 7.64 (d, J = 0.7 Hz, IH), 7.49-7.43 (m, 2H), 7.40 (t, J = 1.1 Hz, IH), 7.34 (m. 2H), 7.02 (d, J = 1.2 Hz, 1 H), 4.86 (d, J = 6.1 Hz, 2H), 3.89 (d, J = 5.9 Hz, 2H), 2.15 (q, J = 7.5 Hz, 2H), 1.93 (s, 6H), 1.12 (t, J = 7.4 Hz, 3H). LCMS m/z 488.38 [M+H]+.

483

Compound	Structure	Method	’HNMR/LCMSmà ΓΜ+Η]+
263	Ox y-oH F	As from compound 125. Larock Method from Cl 17	'HNMR (300 MHz, DMSO-c/6) δ 13.3312.91 (bs, IH), 12.81 (s, IH), 8.07 (d, J = 1.0 Hz, 1 H), 7.927.83 (m, 3H), 7.567.49 (m, 2H), 7.46 (d, J = 1.1 Hz, 1 H), 7.37 -7.22 (m, 4H), 3.13 (s, 2H), 0.96 - 0.87 (m, 2H), 0.59-0.51 (m, 2H); lH NMR (400 MHz, DMSOdb)5 13.10 (s, IH), 12.83 (s, IH), 8.08 (d, J = 1.0 Hz, IH), 7.92-7.90 (m, IH), 7.90 - 7.87 (m, 2H), 7.58 - 7.52 (m, 2H), 7.47 (d, J= 1.1 Hz, 1 H), 7.36 - 7.25 (m, 4H), 3.14 (s, 2H), 0.96-0.88 (m, 2H), 0.58 - 0.49 (m, 2H). LCMS m/z 451.28 [M+H]+.
264	<° o X ° xOsJzXj 12 X 'z	As from compound 125. Larock Method from C117	Ή NMR (300 MHz, DMSO-</6) Ô 13.06 (s, IH), 12.71 (s, IH), 8.13 - 8.06 (m, 2H), 8.04 (d, J = 1.0 Hz, IH), 7.75 - 7.66 (m, 4H), 7.50 (t, J = 8.7 Hz, 2H), 7.42 (t, J = 1.1 Hz, IH), 7.07 (d, J = 1.1 Hz, IH), 4.65 (d, J = 6.4 Hz, 2H), 3.87 (d, J = 6.3 Hz, 2H), 3.46 (s, 2H). LCMS m/z 467.31 [M+H]+.

484

Compound	Structure	Method	‘HNMR/ICMÎMt [M+H]'
265	H VI	C F	λ y oh 00 Λ F	As from compound 125. Larock Method from Cl 17	‘H NMR (300 MHz, DMSO-J6)Ô 13.01 (s, IH), 12.62 (s, IH), 8.10-8.03 (m,2H), 8.00 (d, J= 1.0 Hz, IH), 7.80- 7.72 (m, 2H), 7.72 - 7.62 (m, 2H), 7.48 (t, J = 8.7 Hz, 2H), 7.26 (t, J = 1.1 Hz, IH), 6.98 (d, J = 1.1 Hz, IH), 3.18 (s, 2H), 2.36 - 2.21 (m, 2H), 2.04- 1.87 (m, IH), 1.61 - 1.44 (m, 3H). LCMS m/z 465.33 [M+H]'.
266	H Ν-γί Νχ I	°\ VrV	—-OH J o- Vo Λ F	As from compound 125. Larock Method from Cl 17	Al NMR (300 MHz, DMSO-t/ô) Ô 12.96 (s, IH), 12.66 (s, IH), 8.11 -7.97 (m, 3H), 7.81 -7.73 (m, 2H), 7.69 - 7.59 (m, 2H), 7.53-7.41 (m, 3H), 7.00 (d, J= LI Hz, 1 H), 4.52 (d, 1 = 5.9 Hz, 2H), 3.91 (s,2H), 3.82 (d, J = 5.8 Hz, 2H), 3.40 (s, 3H). LCMS m/z 472.31 [M+H]'.
267	H nVC	A F vrv	y-OH F— F° Λ F	As from compound 125. Larock Method from Cl 17	'H NMR (300 MHz, Acetone-d6) δ 12. ï 911.18 (bs, 2H), 8.248.09 (m,2H), 7.97 (d, J = 1.0 Hz, IH), 7.73 (d, J = 8.0 Hz, 2H), 7.68 - 7.56 (m, 2H), 7.50- 7.37 (m, 2H), 7.07 (t, J =1.1 Hz, IH), 6.93 (d, J = 1.1 Hz, IH), 3.62 (s, 2H), 3.54-3.39 (m, 4H), 3.38 (s, 3H), 1.96 1.85 (m,2H), 1.511.39 (m,2H). LCMS m/z 500.43 [M+H]'.

485

Compound	Structure	Method	'H NMR; LCMSm/z [M+H]+
268'	ci y-οκ O H / \XTV F	As from compound 125. Larock Method from Cl90	'HNMR (300 MHz, DMSOA) ΰ 12.97 (s, IH), 12.58 (s, IH), 8.14-8.07 (m, 2H), 8.00 (d, J= 1.0 Hz, IH), 7.66- 7.55 (m, 4H), 7.55 - 7.44 (m, 2H), 7.28 (t, J = 1.1 Hz, IH), 7.06 (d, J = 1.1 Hz, IH), 2.942.82 (m, IH), 1.52 1.27 (m,2H), 1.18 (d, J = 7.1 Hz, 3H), 0.67 (t, J = 7.3 Hz, 3H). LCMS m/z 428.33 [M+H].
269	Ox V-OH H WrrJ.ho ?— \ΧΓ>Ύ Vo Q ' F	As from compound 125. Larock Method from C190	‘H NMR (300 MHz, DMSO-tZ6) δ 12.51 (s, IH), 8.01 - 7.88 (m, 3H), 7.58 - 7.49 (m, IH), 7.49-7.41 (m, IH), 7.41 - 7.28 (m, 4H), 6.91 (t, J = 1.1 Hz, IH), 6.82 (d, J = 1.0 Hz, IH), 4.49 (s, IH), 3.23 (d, J = 9.7 Hz, 2H), 3.09 (s,3H), L60 - 1.41 (m,2H), 0.70 (t, J = 7.3 Hz, 3H). LCMS m/z 474.38 [M+H]\
270	Οχ V-OH O H \ nXjO—' ^VA F	As from compound 125. Larock Method from Cl90	*H NMR (300 MHz, OMSO-Æ) δ 12.90 (s, IH), 12.64 (s, IH), 8.17-8.06 (m, 2H), 8.02 (d, J = LO Hz, IH), 7.78 - 7.68 (m, 2H), 7.68 - 7.56 (m, 2H), 7.56 - 7.45 (m, 3H), 7.30 (d, J = 1.1 Hz, IH), 2.77 (d, J = 7.3 Hz, 2H), 1.48 1.35 (m, IH), 0.57 (d, J = 6.6 Hz, 6H). LCMS m/z 428.29 [M+H]+.

4S6

Compound	Structure	Method	*H NMR; LCMS m/z [M+H]
271	H hA	Cl· AOH AA 8- F	As from compound 125. Larock Method from Cl 17	Ή NMR (300 MHz, DMSO-rf6)S 12.95 (s, IH), 12.57 (s, IH), 8.16-8.04 (m, 2H), 7.99 (d, J = 1.0 Hz, IH), 7.66- 7.45 (m, 6H), 7.28 (t, J = 1.1 Hz, IH), 7.06 (d, J = 1.1 Hz, IH), 3.07 2.91 (m, IH), 1.45 1.22 (m, 2H), 1.19 (d, J = 7.2 Hz, 3H), 1.06 (p, J = 7.2 Hz, 2H), 0.61 (t, J = 7.3 Hz, 3H). LCMS m/z 442.33 [M+H]+.
272	H A Nd	°yoH Çr A^n V-o F	Suzuki Method. As for compounds 107-111.	‘H NMR (400 MHz, Methanol-J4) δ 8.05 (t, J = 7.9 Hz, IH), 7.97 (d, J= 1.1 Hz, IH), 7.50 (m, 2H), 7.42 (t, J= 1.1 Hz, IH), 7.40- 7.33 (m, 3H), 7.30 (m, IH), 7.04 (d, J = 1.1 Hz, IH), 4.74 (d, J = 5.8 Hz, 2H), 3.90 (d, J = 5.8 Hz, 2H),2.18(q, J = 7.4 Hz, 2H), 1.17 (t, J = 7.4 Hz, 3H). LCMS m/z 474.24 [M+H]\
273	H l'A N χ X	0 Il Al· N A n '—1 F	As from compound 125. Larock Method from Cl 17	Ή NMR (400 MHz, Methanol-δ 8.84 (m, IH), 8.05 (d, J = 4.3 Hz, IH), 7.98 (s, IH), 7.63-7.51 (m, 2H), 7.44 - 7.34 (m, 2H), 7.30 (s, IH), 7.04 (m, IH), 3.11 (s, 2H), 2.85 -2.73 (m, 3H), 2.36 (q, J = 10.8, 10.4 Hz, 2H), 2.01 (q, J = 8.0, 6.4 Hz, IH), 1.96- 1.89 (m, 6H), 1.67 (m, IH), 1.58 (m, 2H). LCMS m/z 512.24 [M+H]+.

487

Compound	Structure	Method	lH NMR; LCMS m/z [M+H]h
274	H A	?,o t --ω O \A °ΑΜΆ \\ //	As from compound 125. Larock Method from Cl 17	'HNMR (400 MHz, MethanolA) δ 8.29 8.13 (m, 2H), 8.01 (s, IH), 7.70-7.58 (m, 4H), 7.42 (m, 2H), 7.37 (s, IH), 7.08 (m, IH), 4.35-4.22 (m, 2H), 3.44-3,34 (m, 2H), 2.09 (s, 3H). LCMS m/z 490.33 [M+H]+.
275	H O	V-OH Ça 0° XX F	Photoredox method See footnote	'HNMR (300 MHz, DMSOA)5 12.68 (s, 2H), 8.16-8.07 (m, 2H), 8.04 (d, J = 1.0 Hz, IH), 7.77-7.70 (m, 2H), 7.70 - 7.61 (m, 2H), 7.56 - 7.47 (m, 3H), 7.31 (d, J = 1.1 Hz, IH), 3.43 3.30 (m, 3H), 3.03 2.91 (m, 3H), 2.05 1.92 (m, IH), 1.691.54 (m, IH), 1.26 1.13 (m, IH), LCMS m/z 456.28 [M+H]+.
276	H N·^ Ό	T O > ° OjX-Ca	Suzuki Method. As for compounds 107-111.	lH NMR (400 MHz, MethanolA) δ 7.97 7.93 (m, IH), 7.92 (m, IH), 7.65 (m, IH), 7.45 (m, 2H), 7.40-7.38 (m, IH), 7.38 - 7,32 (m, 2H), 7.07 (d, J = 1.2 Hz, 1 H), 3.15 (heptet, J = 7.1 Hz, IH), 1.94 (s, 6H), 1.20 (d, J = 7.1 Hz, 6H). LCMS m/z 446.17 [M+H]+,

488

Compound	Structure	Method	’H NMR; LCMS m/z [M+H]
2773	N F<NH2 P' n η \F o H / / nfF, \ ££ TfF FFn Vo A F	From compound 261. Amide coupling with ammonia.	Ή NMR (400 MHz, MethanolF) δ 7.96 (d, J = 1.0 Hz, 1 H), 7.80 (d, J = 0.7 Hz, IH), 7.66 (d, J = 0.7 Hz, IH), 7.50-7.44 (m, 3H), 7.39 - 7.29 (m, 2H), 7.02 (d, J = 1.1 Hz, IH), 4.99 (s, 2H), 4.86 (m, 2H), 3.94 (d, J = 5.9 Hz, 2H), 2.15 (q, J = 7.4 Hz, 2H), 1.13 (t, J = 7.5 Hz, 3H). LCMS m/z 459.22 [M+H]4.

^T Methyl 4-(3-hydroxy-4-methyl-pent-l-ynyl)benzoate is used as the alkyne in the coupling partner. Route involves an élimination step.

²· Compound 275 was prepared from methyl 4-[l-(benzenesulfonyl)-6-bromo-5-(4fluorophenyl)pyrrolo[2,3-f]indazol-7-yl]benzoate and 3-(bromomethyI)tetrahydrofuran by a photoredox coupling reaction, followed by simultaneous removal of the tosyl protecting group and the ester group by treatment with NaOH, Piperidine in THF. Photoredox coupling conditions: Added Bis [2-(2,4-difluorophenyl)-5trifluoromethylpyridine] [2-2'-bipyridyl] iridium hexafluorophosphate (2 mg, 0.002 mmol), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (5 mg, 0.019 mmol) and dichloronickel 1,2-dimethoxyethane (4 mg, 0.01820 mmol) to a vial in a dry box. A mixture of bis(trimethylsilyl)silyl-trimethyl-silane (49 pL, 0.1588 mmol), 2,6dimethylpyridine (37 pL, 0.3194 mmol), 3-(bromomethyl)tetrahydrofuran (250 mg, 1.515 mmol) and methyl 4-[ 1 -(benzenesulfonyl)-6-bromo-5-(4fluorophenyl )pyrrolo [2,3-f] indazol-7-yl] benzoate (91 mg, 0.1484 mmol) dissolved in 1,2-dimethoxyethane (2.5 mL) were added to the first vial via syringe under nitrogen. The mixture was irradiatcd in a Merck Photoreactor at 100% LED power, 4700 RPM fan for 18 hours, then concentrated to dryness under reduced pressure.

HATU reagent was used.

Compounds 278-292

Compounds 278-292 (Table 18) were prepared from S4 as described for the préparation of compounds 18-45.

Table 18. Method ofpréparation, structure and physicochemical data for compounds 278-292

Compound

Structure

Boronate Reagent

'H NMR; LCMS m/z [M+H]4

489

Compound	Structure	Boronate Reagent	1H NMR; LCMS m/z [M+Hf
278	l cP Xj h / < Ύ £ M p ΆΑν ri—/ F	OH I ΝΧ:γΒ'ΟΗ ï I A	'H NMR (400 MHz, MethanolA) δ 8,20 (dd, J = 2.4, 0.8 Hz, IH), 7.97 (d, J = 1.0 Hz, IH), 7.79 (dd, J = 8.5, 2.4 Hz, IH), 7.49 (ddt, J = 8.2, 5.6, 2.8 Hz, 2H), 7.45 - 7.33 (m, 2H), 7.22 (t, J = 1.1 Hz, IH), 7.13 (d, J = 1.2 Hz, IH), 6.99 (dd, J = 8.4, 0.8 Hz, IH), 4.60 - 4.46 (m, 2H), 3.89 3.73 (m, 4H), 3.46 (s, 3H), 3.20 (td, J = 11.8, 2.2 Hz, 2H), 2.97 (tt, J = 12.0, 3.7 Hz, IH), 1.77 (qd,J= 12.4, 12.0, 4.3 Hz, 2H), 1.67 (d, J = 12.4 Hz, 2H). LCMS m/z 487.21 [M+H]+.
279	xX H / Ν-ύΑΑ-Α /—ri NJ X !L M P 'A;An ri-/ F	o x	‘H NMR (400 MHz, Methanol-^) δ 8.48 (dd, J = 8.6, 0.8 Hz, IH), 8.46 (dd, J = 2.3, 0.8 Hz, IH), 7.95 (d, J = 1.1 Hz, IH), 7.90 (dd, J = 8.6, 2.4 Hz, IH), 7.53 - 7.46 (m, 2H), 7.37 (m, 2H), 7.25 (t, J = 1.1 Hz, IH), 7.13 (d, J = 1.1 Hz, IH), 4.26 - 4.18 (ni, 2H), 3.81 (dd, J = 11.5, 4.0 Hz, 2H), 3.27 - 3.15 (m, 2H), 3.07 - 2.90 (m, IH), 2.72 (ni, 2H), 2.22 (p, J = 7.7 Hz, 2H), 1.78 (m, 2H), 1.69 (d, J = 12.9 Hz, 2H). LCMS m/z 496.2 [M+H]+.

490

Compound	Structure	Boronate Reagent	' H NMR; LCMS m/z [M+H]1
280	F F r O Xa H n—^\A /—. A X L / \ p F	LL y-\ O 0- O—U P>—cû AA 'o x	lH NMR (400 MHz, Méthanol A) δ 8.26 (dd, J = 2.4, 0.8 Hz, IH), 7.97 (d, J = 1.1 Hz, IH), 7.86 (dd, J = 8.4, 2.4 Hz, IH), 7.55 7.46 (m, 2H), 7.43 7.35 (m, 2H), 7.22 (t, J = 1.1 Hz, IH), 7.13 (d, J= 1.1 Hz, IH), 7.08 (dd, J = 8.4, 0.8 Hz, IH), 4.96 (q, J = 8.8 Hz, 2H), 3.89 - 3.70 (m, 2H), 3.20 (td, J = 11.7, 2.3 Hz, 2H), 2.97 (tt, J = 12.0, 3.8 Hz, IH), 1.76 (qd, J = 12.2, 11.7, 4.2 Hz, 2H), 1.68 (d, J = 13.1 Hz, 2H). LCMS m/z 511.19 [M+H]+.
281	O N A VJ H / ΑΑ·Α\ /-\ X X ί XX p ^-ΆΑ^Ν \--/ F	P R J)__	'H NMR (400 MHz, MéthanolA) δ 7.97 (d, J = 1.1 Hz, IH), 7.79 (d, J = 2.4 Hz, IH), 7.65 (dd, J = 9.1, 2.5 Hz, IH), 7.48 (m, 2H), 7.43 - 7.36 (m, 2H), 7.30 (t, J= 1.1 Hz, IH), 7.13 (d, J = 1.1 Hz, IH), 6.73 (dd, J = 9.2, 0.6 Hz, IH), 3.95-3.78 (m, 2H), 3.70 (s, 3H), 3.24 (td, J = 11.8, 2.0 Hz, 2H), 2.97 (tt, J = 12.1, 3.6 Hz, IH), 1.84 (qd, J = 12.5, 4.3 Hz, 2H), 1.76 - 1.63 (m, 2H). LCMS m/z 443.19 [M+H]+.

491

Compound	Structure	Boronate Reagent	'H NMR; LCMS m/z [M+Hf
282	0 ΗνΎ nV O H Z NAAf / \ N I || f—( 0 +AAn x 7 X F	X°' /=\ 1 1 LL Υγ ; ΑΌ A 2 O	'H NMR (400 MHz, MethanolA) δ 8.40 (dd, J = 2.3, 0.8 Hz, IH), 8.26 (d, J = 8.5 Hz, IH), 7.98 (d, J = 1.1 Hz, IH), 7.89 (dd, J = 8.5,2.3 Hz, IH), 7.57 - 7.47 (m, 2H), 7.40 (t, J = 8.6 Hz, 2H), 7.25 (t, J = 1.1 Hz, IH), 7.14 (d, J = 1.1 Hz, IH), 3.81 (dd, J = 11.3, 4.1 Hz, 2H), 3.26 - 3.16 (m, 2H), 3.07 - 2.90 (m, IH), 2.24 (s, 3H), 1.79 (qd, J = 12.3, 11.7, 4.2 Hz, 2H), 1.70 (d, J = 12.9 Hz, 2H). LCMS m/z 470.19 [M+Hf.
283	V# H n' ] |[ VA 0 \—/ p F	Q Ô HO^'OH	‘H NMR (400 MHz, Chloroform-d ) δ 8.20 (dd, J = 2.4, 0.8 Hz, IH), 7.94 (d, J = 1.2 Hz, IH), 7.49 (dd, J = 8.6, 2.3 Hz, IH), 7.39 - 7.30 (m, 2H), 7.27 (t, J= L1 Hz, IH), 7.25 - 7.19 (m, 2H), 7.05 (d, J = 1.1 Hz, IH), 6.47 (dd, J = 8.7, 0.8 Hz, IH), 3.88 3.68 (m, 2H), 3.61 3.39 (m, 4H), 3.15 (td, J = 11.8, 1.8 Hz, 2H), 2.86 (tt, J = 12.3, 3.5 Hz, IH), 2.07 - 1.91 (m, 4H), 1.79 (qd, J = 12.5, 4.3 Hz, 3H), 1.62 - 1.45 (m, 2H). LCMS m/z 482.25 [M+Hf.

492

Compound	Structure	Boronate Reagent	'hxmrhcmsa [M+Hf
284	—OH O H / N-—Aj-A /—\ n J A / \ P A-ΆΑ^Ν x—7 ô F	hobAh	*H NMR (400 MHz, Methanol-A) δ 7.96 (d, J = 1.1 Hz, IH), 7.59 7.44 (m, 7H), 7.44 7.33 (m, 2H), 7.23 (t, J = 1.1 Hz, IH), 7.11 (d, J = 1.2 Hz, IH), 4.73 (s, 2H), 3.78 (dd, J = 11.6, 4.1 Hz, 2H), 3.23 - 3.12 (m, 2H), 3.01 (tt, J = 12.2, 3.5 Hz, IH), 1.83 (dd, J = 12.8, 4.3 Hz, 2H), 1.66 (d, J = 13.0 Hz, 2H). LCMS m/z 442 [M+H]+.
285	γΝ^0 H / ΝΆχΧ. /—\ Nk 1 L A p x^AA^n x—7 F		lH NMR (400 MHz, Methanol·^ + CDC13) δ 7.94 (d, J = 1.0 Hz, IH), 7.89 (s, IH), 7.44 (m, 2H), 7.39 - 7.31 (m, 3H), 7.09 (d, J = 1.2 Hz, IH), 5.38 (m, IH), 4.78 - 4.70 (m, 2H), 4.59 - 4.50 (m, IH), 4.46 (dd, J = 10.6, 5.5 Hz, IH), 3.85 (dd, J = 11.7, 4.1 Hz, 2H), 3.25 (m, 2H), 3.01 (m, IH), 1.98 (s, 3H), 1.96 - 1.82 (m, 2H), 1.67 (d, J = 13.1 Hz, 2H). LCMS m/z 499.31 [M+H]+.
o A\ 1 ° yaa z A \o
286	O o 1 D i 1 t l 1 | I z~h T AA—l- Z	0^,C A Gn 0-/ XAj°	)	fH NMR (400 MHz, Methanol-A) § 7.96 (d, J = 1.0 Hz, IH), 7.94 (d, J = 0.9 Hz, IH), 7.78 (d, J = 0.8 Hz, IH), 7.50 - 7.43 (m, 2H), 7.42 - 7.33 (m, 3H), 7.10 (d, J = 1.2 Hz, IH), 5.43 (tq, J = 8.1, 5.3 Hz, IH), 4.94 (m, IH), 4.87 - 4.79 (m, IH), 4.63 - 4.43 (m, 2H), 4.41 - 4.30 (m, IH), 3.92 - 3.76 (m, 2H), 3.28 - 3.19 (m, 2H), 3.02 (tt, J = 12.3, 3.5 Hz, IH), 1.90

493

Compound	Structure	Boronate Reagent	1H NMR; LCMS m/z [Μ+ΗΓ
			(qd, J = 12.6, 4.3 Hz, 2H), 1.68 (d, J = 12.9 Hz, 2H), 1.40 (d, J = 6.8 Hz, 3H). LCMS m/z 529.38 [M+H]+,
287	° 1 Q χν IZ P Z	\/O O®^ O Vah~X	‘H NMR (400 MHz, Methanol-Æf) δ 7.96 (d, J = 1.1 Hz, IH), 7.95 (d, J = 0.8 Hz, IH), 7.78 (d, J = 1.1 Hz, IH), 7.47 (m, 2H), 7.42 - 7.33 (m, 3H), 7.10 (d, J = 1.1 Hz, IH), 5.51 5.35 (m, IH), 4.94 (m, 1 H), 4.83 (m, 1 H), 4.65 - 4.43 (m, 2H), 4.36 (q, J = 6.S Hz, IH), 3.84 (dd, J = 11.6, 4.0 Hz, 2H), 3.28 - 3.21 (m, 2H), 3.02 (m, IH), 1.90 (qd, J = 12.6, 4.3 Hz, 2H), 1.68 (d, J = 12.4 Hz, 2H), 1.40 (d, J = 6.8 Hz, 3H). LCMS m/z 529.38 [M+H]+.
288	nX A H [ ΛΑ n . 1 L / \ P A^N V_/ X F	HO. O HO OH	Ή NMR (400 MHz, Methanol-^) δ 8.63 8.56 (m, IH), 8.06 7.95 (m, 2H), 7.75 (d, J = 7.9 Hz, IH), 7.58 7.49 (m, 2H), 7.41 (dd, J = 9.3, 8.0 Hz, 2H), 7.24 (t, J= 1.1 Hz, IH), 7.15 (d, J = 1.1 Hz, IH), 4.84 (s, 2H), 3.80 (dd, J = 11.1, 3.8 Hz, 2H), 3.35 (s, IH), 3.21 (td, J = 11.5, 2.8 Hz, 2H), 3.01 (tt, J = 11.4, 4.2 Hz, IH), 1.74 (dd, J = 11.3, 3.8 Hz, 3H). LCMS m/z 443 [M+H]+.

494

Compound	Structure	Boronate Reagent	'h NMR; LCMS m/z [M+H]+
289	H n0	O. ΑΝΗ2 / N Xa CAA—( p F	O. o Me OT A	Ή NMR (400 MHz, DMSOA) δ 12.62 (s, IH), 8.55 (d, J = 2.0 Hz, IH), 8.19 - 8.08 (ni, IH), 8.Ü2 (s, IH), 7.89 (d, J = 2.0 Hz, IH), 7.62 (m, 2H), 7.58 - 7.47 (m, 3H), 7.24 (s, IH), 7.10 (s, IH), 3.83 - 3.67 (m, 2H), 3.18 3.06 (m, 2H), 2.99 (m, IH), 2.67 (s, 3H), 1.66 (m, 4H). LCMS m/z 416.31 [M+H] \
290	H	N. /\zNH5 X N γ 2 \V O A/~O F	OEt 0=^ n-n A	lH NMR (400 MHz, DMSOA) δ 12.64 (s, IH), 7.98 (s, IH), 7.94 (s, IH), 7.64 (s, IH), 7.60 - 7.53 (m, 3H), 7.49 (t, J = 8.6 Hz, 2H), 7.38 (s, IH), 7.32 (s, IH), 7.03 (s, IH), 3.86 - 3.66 (m, 2H), 3.17 (t, J = 11.5 Hz, 2H), 3.102.95 (m, IH), 1.74 (dd, J = 14.1, 10.1 Hz, 2H), 1.63 (d, J = 12.8 Hz, 2H). LCMS m/z 459.35 [M+H]+,
2911	H N·^ Ο D	ovoh O ΑΤλΑ 3 Q F	See footnote 1	‘H NMR (300 MHz, DMSO A) δ 13.1212.82 (bs, IH), 12.57 (s, IH), 8.17 - 8.05 (m, 2H), 7.71 - 7.57 (m, 4H), 7.57 - 7.44 (m, 2H), 7.26 (d, J = 1.2 Hz, IH), 7.07 (d, J = 1.1 Hz, IH), 3.73 (d, J = 11.0 Hz, 2H), 3.18 2.93 (m, 3H), 1.77 1.56 (m, 4H). LCMS m/z 457.36 [M+H]+,

495

Compound	Structure	Boronate Reagent	!H NMR; LCMS m/z [M+H]+
292 1. XX	μ X AH va ° H / naA, /—\ AΎ JW p F	OMe n-n A	Ή NMR (400 MHz, Methanol-cl]) δ 7.93 (d, J = 1.0 Hz, IH), 7.84 (m, IH), 7.65 (m, IH), 7.42 (m, 2H), 7.39 (t, J = 1.1 Hz, IH), 7.36 7.29 (m, 2H), 7.08 (d, J = 1.1 Hz, IH), 3.85 (dd, J = 11.5, 4.1 Hz, 2H), 3.29 - 3.18 (m, 2H), 3.00 (tt, J = 12.3, 3.5 Hz, IH), 1.95 (s, 6H), 1.88 (qd, J = 12.6, 4.3 Hz, 2H), 1.66 (d, J = 12.6 Hz, 2H). LCMS m/z 488.21 [M+H]+. |

. A of compound 33 ( 100 mg) was in MeOD (14 mL) was treated with NaH. The mixture was sealed in a vial and heated at 70 °C for 3 days. The mixture was concentrated, diluted with DMSO-D6 (3 mL) and D₂O (0.25 mL ) and injected on a CIS column. Purification by reversed-phase chromatography (Column: Cl8. Gradient: l 0-100 % MeCN in water with 0.1 % formic acid) afforded the product.

496

Compounds 293 and 294 (2S, 3S, 4S, 5R)-6-(7-(4-carboxyphenyl)-5-(4-fluorophenyl)-6-(tetrahydro-2H-pyran-4yl)pyrrolo[2,3-f] indazol-2(5H)-yl)-3,4,5-trihydroxytetrahydro-2H-6l3-pyran-2-carboxvlic acid (293) and (2S,3S,4S,5R)-6-(7-(4-carboxyphenyl)-5-(4-fluorophenyl)-6-(tetrahydro-2H5 pyran-4-yl)pyrrolo[2,3-f] indazol-1 (5H)-yl)-3,4,5-trihydroxytetrahydro-2H-6l3-pyran-2carboxylic acid (294)

Benzene (11 mL) was added to a mixture of methyl (2S,3S,4S,5R,6R)-3,4,5-triacetoxy-610 bromo-tetrahydropyran-2-carboxyIate (1.13 g, 2.845 mmol), 4-[5-(4-fluorophenyl)-6tetrahydropyran-4-yl-lH-pyrrolo[2,3-f]indazol-7-yl]benzoic acid 33 (281 mg, 0.62 mmol), and Ag2O₃ (851 mg, 3.09 mmol). The mixture was stirred overnight at 70 °C în a sealed vial under nitrogen. The mixture was concentrated to dryness. Methanol (11 mL) and THF (11 mL) were added and then a solution of LiOH (3.1 mL of 2 M, 6.2 mmol). The mixture was stirred 15 overnight at room temperature. The mixture was fdtered through a pad of Celite® and washed the plug with additional THF and Methanol. The reaction mixture was concentrated to dryness under reduced pressure.

The mixture was diluted with ~8 mL of DMSO:water (3:1) and injected on a C18 150 g column. Purification by reversed-phase chromatography (Column: C18. Gradient: 10

497 %acetonitrile in water, then isocratîc at 45 % MeCN in water until the compound dûtes and finally 100% ACN ail with 0.1 % formic acid) afforded two peaks. The first eluting peak corresponded to compound 293 and the second eluting peak corresponded to compound 294.

Compound 293 (peak 1) (2S,3S,4S,5R)-6-(7-(4-carboxyphenyl)-5-(4-fluorophenyl)-6(tetrahydro-2H-pyran-4-yl)pyrrolo[2,3-f|indazol-2(5H)-yl)-3,4,5-trihydroxytetrahydro-2H-613pyran-2-carboxylic acid 293 (167.0 mg, 42 %). 'H NMR (300 MHz, DMSOA) S 12.94 (s, 2H), 8.45 (s, IH), 8.18 - 8.05 (m, 2H), 7.72 - 7.58 (m, 4H), 7.52 (t, J = 8.7 Hz, 2H), 7.46 - 7.38 (m, IH), 6.97 (d,J= 1.3 Hz, IH), 5.60 (d, J = 9.2 Hz, IH), 5.53-5.21 (m, 3H), 4.06 - 3.84 (m, 2H), 3.82 - 3.64 (m, 2H), 3.59 - 3.37 (m, 2H), 3.20 - 3.05 (m, 2H), 3.05 - 2.91 (m, 1 H), 1.77 - 1.53 (m, 4H). LCMS m/z 632.36 [M+H]⁺.

Compound 294 (peak 2) (2S,3S,4S,5R)-6-(7-(4-carboxyphenyl)-5-(4-fluorophenyl)-6(tetrahydro-2H-pyran-4-yl)pyrrolo[2,3-f| indazol-l(5H)-yl)-3,4,5-trihydroxyt etrahydro-2H-613pyran-2-carboxylic acid 294 (7.1 mg, 2 %). ‘H NMR (300 MHz, DMSOA) δ 13.12-12.7 (bs, 2H), 8.18 - 8.07 (m, 3H), 7.70 - 7.57 (m, 4H), 7.57 - 7.46 (m, 3H), 7.13 - 7.08 (m, IH), 5.79 (d, J = 8.9 Hz, IH), 5.25 - 4.96 (m, 3H), 4.03 (d, J = 8.0 Hz, 2H), 3.72 (d, J = 10.9 Hz, 2H), 3.45 (s, 2H), 3.10 (s, 3H), 1.65 (s, 4H). LCMS m/z 632.36 [M+Hf.

Compounds 295-297

Compounds 295-297 were prepared as described in Table 19 with modifications noted in the footnotes.

Table 19. Method ofpréparation, structure and physicochemical data for compounds 295-297

Compound	Structure	Method	TH NMR; LCMS m/z [M+Hf
2951	y oh O H NA+A. <CQa F	As for compound 255. Larock method from Cl90.	‘H NMR (300 MHz, DMSOA) δ 12.90 (s, IH), 12.64 (s, IH), 8.17 - 8.06 (m, 2H), 8.02 (d, J = 1.0 Hz, IH), 7.73 - 7.67 (m, 2H), 7.67 - 7.59 (m, 2H), 7.58 - 7.55 (m, IH), 7.50 (t, J = 8.7 Hz, 2H), 7.27 (d, J = 1.1 Hz, IH), 2.80 (t, J = 7.8 Hz, 2H), 1.35 - 1.20 (m, 2H), 1.09 - 0.87 (m, 6H), 0.74 - 0.64 (m, 3H). LCMS m/z 456.33 [M+Hf.

498

296	H nX		o. A-oh A Anh . oA F	See faotnote 2	]H NMR (300 MHz, DMSOA) δ 12.77 (s, 2H), 9.98 (s, IH), 8.13 - 8.01 (m, 3H), 7.84 - 7.70 (m, 3H), 7.57 - 7.39 (m, 5H), 2.12 (q, J = 7.6 Hz, 2H), 0.89 (t, J = 7.6 Hz, 3H). LCMS m/z 443.28 [M+H]+.
			Οχ A-OH
297	H	An'	A‘^	See footnole 3	LCMS m/z 444.19 [M+Hf·
1. ,		v	F

was used as the alkyne in the Larock indole

ΙΟ cyclization. A réduction step using Et₃SiH and Nal was applied prior to treatment with NaOH. See compound 176 for an analogous method.

Prepared from Buchwald amination of methyl 4-[l-(benzenesulfonyl)-6-bromo-5-(4fluorophenyl)pyrrolo[2,3-fjindazol-7-yl]benzoate with propenamide. Conditions: XantPhos Pd G3, Cs₂CO₃ in 1,4-dioxane at 110 °C. Methyl 4-[l-(benzenesulfonyl)-6bromo-5-(4-fluorophenyl)pyrrolo[2,3-f]indazol-7-yl]benzoate was prepared in an analogous fashion to C149.

³' Compound 297 was prepared by Larock cyclization between 6-bromo-N-(4fluorophenyl)-l-tetrahydropyran-2-yl-indazol-5-amine and ethyl 4-(3-hydroxyprop-lynyl)benzoate. The resulting intermediate ethyl 4-[5-(4-fluorophenyl)-6(hydroxymethyl)-l-tetrahydropyran-2-yl-pyrrolo[2,3-f]indazol-7-yl]benzoate was alkylated with îodopropane. Ester hydrolysis with NaOH, followed by treatment with HCl to remove the THP protecting group afford compound 297.

499

Compound 298

4-[5-benzyl-6-(2-cyano-I,l-dimethyl-ethyl)-lH-pyrrolo[2,3-j]indazol-7-yl]benzoic acid

Cl 84

Step I, methyl 4-[6-(2-cyano-l, l-dimethyl-ethyl)-l-tetrahydropyran-2-yl-5H-pyrrolo[2,3f]indazol-7-yl]benzoate (C192)

6-bromo-l-tetrahydropyran-2-yl-indazol-5-amine (674 mg, 2.119 mmol), methyl 4-(4cyano-3,3-dimethyl-but-l-ynyl)benzoate (1.00 g, 4.1 mmol), Pd(PtBu₃)₂ (110 mg, 0.22 mmol) were suspended in 1,4-dioxane (13 mL). Then, N-cyclohexyl-N-methyl-cyclohexanamine (1.2 mL, 5.6 mmol) was added. The reaction was heated at S5 °C for 18 h and under nitrogen. Water and CH2CI2 were added. The mixture was extracted with CH2CI2 (3 x), The organic phases were passed through a phase separator, combined and concentrated in vacuo. The crude was purified by flash column chromatography (12 g silica gel, 0-3 % of MeOH in CH2CI2). A light brown solid was obtained, methyl 4-[6-(2-cyano-l,l-dimethyl-ethyl)-l-tetrahydropyran-2-yl-5Hpyrrolo[2,3-f] indazol-7-yI] benzoate (776.0 mg, 76 %). 'H NMR (400 MHz, DMSO4) δ 11.01 (s, IH), 8.11 (d, J = 0.9 Hz, IH), 8.10 - 8.06 (m, 2H), 7.69 (d, J = 1.1 Hz, IH), 7.64 - 7.50 (m, 2H), 7.04 (s, IH), 5.70 (m, IH), 3.91 (s, 3H), 3.74 (m, IH), 3.59 (m, IH), 2.90 (s, 2H), 2.40 (m, IH), 1.98 (m, IH), 1.87 (m, IH), 1.71 (m, IH), 1.49 (m, 2H), 1.38 (m, 6H). LCMS m/z 457.28 [M+H]⁺.

500

Step 2. methyl 4-[5-benzyl-6-(2-cyano-l, 1-dimethyl-ethyl)-l-tetrahydropyran-2-yl-pyrrolo [2,3f]indazol-7-yl] benzoate (Cl93)

Methyl 4-[6-(2-cyano-l, l -dimethyl-ethyl)-1 -tetrahydropyran-2-yl-5H-pyrroIo[2,3f]indazol-7-yl]benzoate (20 mg, 0.042 mmol) was dissolved in DMF (208.1 pL). Then, Et₃N (9 pL, 0.065 mmol) was added, followed by benzyl bromide (7.5 pL, 0.063 mmol) and the reaction was stirred for 90 minutes at room température. This mixture was advanced to the next step without further purification.

Step 3. Synthesis of 4-[5-benzyl-6-(2-cyano-l,l-dimethyl-ethyl)-lH-pyrrolo[2,3-f]indazol-7yl]benzoic acid (298)

Part A: To a solution of methyl 4-[5-benzyl-6-(2-cyano-l,l-dimethyl-ethyl)-ltetrahydropyran-2-yl-pyrrolo[2,3-f]indazoI-7-yl]benzoate Cl93 (40 mg, 0.073 mmol) in DMF (0.4 mL) was added a solution of HCI (200 pL of 4 M, 0.8 mmol) in dioxane. The mixture was stirred for approximately two weeks. Water and CH2CI2 were added. The mixture was extracted with CH2CI2 (3 x). The organic phases were passed through a phase separator, combined and concentrated in vacuo to afford methyl 4-[5-benzyl-6-(2-cyano-l,l -dimethyl-ethyl )-lHpyrrolo[2,3-f]indazol-7-yl]benzoate. LCMS m/z 463.35 [M+H]⁺.

Part B: Methyl 4-[5-benzyl-6-(2-cyano-l,l-dimethyl-ethyl)-lH-pyrrolo[2,3-f]indazol-7yl]benzoate was suspended in EtOH (0.3 mL) and an aqueous solution of NaOH (100 pL of 2 M, 0.20 mmol) was added. The mixture was heated at 60 °C for 48 h. Aqueous HCl 1.0 M and CH2CI2 were added. The mixture was extracted with CH2CI2 (3 x). The organic phases were passed through a phase separator, combined, and concentrated in vacuo. Purification by reverscd-phase HPLC. Method: Cl8 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H₂O with 0.1 % trifluoroacetic acid afford the products as a white solid. 4-[5-benzyl-6(2-cyano-1,1-dimethyl-ethyl)-lH-pyrrolo[2,3-f]indazol-7-yl]benzoic acid (Trifluoroacetate sait) (6.1 mg, 15 %). 'H NMR (400 MHz, MethanolF) δ 8.20 - 8.10 (m, 2H), 8.04 (d, J = 1.1 Hz, 1 H), 7.66 - 7.55 (m, 2H), 7.40 (d, J = 1.2 Hz, IH), 7.34-7.25 (m, 2H), 7.26 - 7.18 (m, IH), 7.04 - 6.93 (m, 3H), 5.80 (s, 2H), 2.86 (s, 2H), 1.47 (s, 6H). LCMS m/z 449.33 [M+Hf.

Compounds 299-305

Compounds 299-305 (Table 20) were made according to the route described for compound 298 using various alkylating agents for alkylation of intennediate C192.

501

Table 20. Method ofpréparation, structure and physicochemical data for compounds 299-305

Compound	Structure	Alkylating Agent	lH NMR; LCMS m/z [M+H]
				’H NMR (400 MHz, Methanol A) Ô 8.18 -
		ys	Bv	8.12 (m, 2H), 8.03 (d, J
	H			= 1.1 Hz, IH), 7.64 -
299	N			7.57 (m, 2H), 7.40 (d, J
	L VY +- N c—=N	9 F	= 1.2 Hz, IH), 7.11 6.92 (m, 5H), 5.79 (s, 2H), 2.87 (s, 2H), 1.47
		yx		(s, 6H). LCMS m/z
	f'			467.3 [M+H]+.
		HO AO		πΗ NMR (400 MHz, Methanol-A δ 8.21 -
	H N N |	O	Br	8.07 (m, 2H), 7.98 (d, J = 1.1 Hz, IH), 7.66 - 7.58 (m, 2H), 7.38 (d, J = 1.2 Hz, IH), 7.30 (m,
300	AA	An '—=n		IH), 7.01 - 6.92 (m, 2H), 6.80 (d, J = 7.9
	F—	o	F	Hz, IH), 6.73 (d, J = 9.8 Hz, IH), 5.81 (s, 2H), 2.87 (s, 2H), 1.47 (s, 6H). LCMS m/z 467.34 [M+Hf.
		HO, AO O		Ή NMR (400 MHz, MethanolA) δ 8.22 8.10 (m, 2H), 7.96 (d, J
	H Na N \		= 1.0 Hz, IH), 7.66 7.55 (m, 2H), 7.38 (d, J = 1.1 Hz, IH), 7.27 (m,
' [£α
	AA	AA 8-ξν		IH), 7.20 (m,z IH),
		AA F	F Br	6.97 (t, J = 1.2 Hz, IH), 6.97 - 6.90 (ni, IH), 6.41 (td, J = 7.8, 1.6 Hz, IH), 5.80 (s, 2H),
301				2.85 (s, 2H), 1.46 (s, 6H); ’H NMR (400 MHz, MethanolA) δ 8.20 - 8.10 (m, 2H), 7.98 (d, J = 1.1 Hz, IH), 7.68 - 7.57 (m, 2H), 7.40 (d, J = 1.2 Hz, IH), 7.33 - 7.24 (m, IH), 7.20 (ddd, J = 10.5, 8.3, 1.2 Hz, IH), 6.99 - 6.92 (m, 2H), 6.46 - 6.37 (m, IH),

502

Compound	Structure	Alkylating Agent	*H NMR; LCMS m/z [M+H]
			5.82 (s, 2H), 2.86 (s, 2H), 1.47 (s, 6H). LCMS m/z 467.315 [M+H]+.
302	HO ao O h / i xXjXa \--— N F \	F Br Ol AA-F	lH NMR (400 MHz, MethanolA) δ 8.21 8.09 (m, 2H), 7.96 (d, J = 1.1 Hz, IH), 7.63 7.54 (m, 2H), 7.38 7.25 (m, 2H), 6.99 6.88 (m, 3H), 5.87 (s, 2H), 2.99 (s, 2H), 1.55 (s, 6H). LCMS m/z 485.44 [M+Hf.
303	z C 'zi Tl K/ fri o T II z	i Br θ'	'H NMR (400 MHz, Methanol-A) δ 8.19 8.10 (m, 2H), 7.96 (d, J = 1.1 Hz, IH), 7.67 7.57 (m, 2H), 7.31 (d, J = 1.1 Hz, IH), 7.27 (d, J = 7.5 Hz, IH), 7.13 (td, J = 7.5, 1.3 Hz, IH), 6.97 (t, J = 1.1 Hz, IH), 6.94 (dd, J = 8.1, 6.9 Hz, IH), 6.29-6.19 (m, IH), 5.68 (s, 2H), 2.84 (s, 2H), 2.54 (s, 3H), 1.45 (s, 6H). LCMS m/z 463.41 [M+H]+.
304	HO. ao O ri n-aaJ I <VAAn		'H NMR (400 MHz, Methanol-d4) δ 8.21 8.09 (m, 2H), 7.97 (d, J = 1.1 Hz, IH), 7.67 7.57 (m, 2H), 7.51 (dd, J = 8.0, 1.2 Hz, IH), 7.34 (d, J = 1.2 Hz, IH), 7.25 (td, J = 7.7, 1.6 Hz, IH), 7.09 (td, J = 7.6, 1.2 Hz, IH), 6.98 (t, J= 1.1 Hz, 1 H), 6.38 (dd, J = 7.8, 1.6 Hz, IH), 5.77 (s, 2H), 2.82 (s, 2H), 1.45 (s, 6H); *H NMR (400 MHz, MethanolA) δ 8.25 8.09 (m, 2H), 7.99 (d, J = 1.1 Hz, IH), 7.72 -

503

Compound	Structure	Alkylating Agent	'H NMR; LCMSm/z [M+H]+
			7.58 (m, 2H), 7.52 (dd, J = 8.0, 1.2 Hz, IH), 7.35 (d, J = 1.2 Hz, IH), 7.26 (td, J = 7.7, 1.6 Hz, IH), 7.10 (td, J = 7.5, 1.2 Hz, 1 H), 6.98 (t, J= 1.1 Hz, 1 H), 6.38 (dd, J = 7.8, 1.5 Hz, IH), 5.78 (s, 2H), 2.83 (s, 2H), 1.46 (s, 6H). LCMS m/z 483.34 [M+H]\
305	Hy° O H ùXXAç /—=N Al ΑΧΌ \	.Br \ I M	‘H NMR (400 MHz, Methanol-c/4) δ 8.23 8.08 (m, 2H), 7.98 (d, J = 1.1 Hz, IH), 7.67 7.57 (m, 2H), 7.35 (d, J = 1.1 Hz, IH), 7.23 (ddd, J = 9.0, 7.4, 1.7 Hz, IH), 7.07 (dd, J = 8.3, LI Hz, IH), 6.97 (t, J= 1.1 Hz, IH), 6.72 (td, J = 7.5, L1 Hz, IH), 6.28 (dd, J = 7.6, 1.6 Hz, IH), 5.68 (s, 2H), 4.01 (s, 3H), 2.81 (s, 2H), 1.45 (s, 6H). LCMS m/z 479.44 [M+H]+.

504

Compound 306

4-(6-(l-cyano-2-methylpropan-2-yl)-5-(thioph en-2-ylmethyl) -1,5-dihydropyrrolo [2,3-f] indazol7-yl)benzoic acid (306)

NaCNBH₃, dîchloromethane 80 °C

C194

2. NaOH

Part A: 6-bromo-lH-indazol-5-amine (20 mg, 0.094 mmol), thiophene-2-carbaldehyde (approximately 12.70 mg, 0.11 mmol), Pd(tBu₃P)₂ (5 mg, 0.01 mmol), polymer supported acetic acid (10 pL, 0.18 mmol) were suspended in DCE (0.3 mL). The reactions were heated at 80 °C for 18 h. The reaction mixture was fïltered, and the beads washed with methanol. The mixture was concentrated in vacuo and the crude product C194 was advanced to the next step without further purification.

Part B: The crude product C194 and methyl 4-(4-cyano-3,3-dimethyl-but-l ynyl)benzoate (35 mg, 0.15 mmol) were suspended în Dioxane (0.4 mL), then NaOH (200 pL of 1 M, 0.20 mmol) was added. A current of nitrogen was blown through the reaction vial, and N-cyclohexyl-N-methyl-cyclohexanamine (50 pL, 0.23 mmol) was added. The reaction was heated at 110 °C for 24 h.

Part C: An aqueous solution of NaOH (200 pL of 1 M) was added to the reactions and the mixtures were heated at 60 °C for 5 h. After this time LC-MS chromatogram was obtained to confinn the formation of product. Water and CHC1₃:IPA (3:1) were added. The mixture was extracted with CHC1₃:IPA (3:1 ) (3 x). The organic phases were passed through a phase separator, combined and concentrated in vacuo. Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H₂O with 0.2 % formic 505 acid afford the product. *H NMR (400 MHz, Méthanol-^) δ 8.10 - 8.01 (m, 2H), 7.99 (d, J = l.l Hz, IH), 7.53 (d, J = 1.2 Hz, IH), 7.49 - 7.42 (m, 2H), 7.27 (dd, J = 5.1, 1.2 Hz, IH), 6.96 (t, J = 1.1 Hz, IH), 6.92 (dd, J = 5.1, 3.5 Hz, IH), 6.72 (dd, J = 3.5, 1.3 Hz, IH), 5.90 (s, 2H), 2.87 (s, 2H), 1.51 (s, 6H). LCMS m/z 455.29 [M+H]⁺.

Compounds 307-319

Compounds 307-319 (Table 21) were prepared using the method described for the préparation of compound 306.

Table 21. Method ofpréparation, structure, physicochemical data for compounds 307-319

Compound	Structure	Aldéhyde or ketone reagent/Method	*HNMR; LCMSfli/z[M+H]+
307	HO O H K na+A i λ--=N O—	O J] As for compound 306	A NMR (400 MHz, Chlorofonn A) δ 8.20 (d, J = 7.9 Hz, 2H), 8.18-8.14 (m, IH), 7.62 (d, J = 1.0 Hz, IH), 7.53 (d, J = 7.9 Hz, 2H), 7.03 (s, IH), 4.31 (d, J = 7.4 Hz, 2H), 3.98 (dd, J = 11.2, 4.0 Hz, 2H), 3.33 (dd, J= 12.5, 10.2 Hz, 2H), 2.72 (s, 2H), 2.51 -2.33 (m, IH), 1.59 (s,6H), 1.57 - 1.39 (m, 4H). LCMS m/z 45ΊΑ5 [M+H]+.
308	Z II T ° \ J \ / IZ fl Z	O /N J oyç As for compound 306	H NMR (400 MHz, Méthanol A) δ 8.15 8.11 (m, 2H), 8.11 (d, J = 1.1 Hz, IH), 7.59 - 7.51 (m, 3H), 6.96 (t, J = 1.1 Hz, IH), 4.63 (s, 2H), 4.29 4.15 (m, 2H), 3.70 3.49 (m, 2H), 2.86 (s, 2H), 1.46 (s, 6H), 1.29 (s, 3H). LCMS m/z 443.19 [M+H]\

506

Compound	Structure	Aldéhyde or ketone re agent/Method	'HNMR; LCMS/m/z [M+H]'
309	HO yo Fj H / N \—=N J	J As for compound 306	lH NMR (400 MHz, Methanol-A) δ 8.14 (d, J = 1.0 Hz, IH), 8.13 - 8.08 (m, 2H), 7.73 (d, J = 1.2 Hz, IH), 7.56 - 7.46 (m, 2H), 6.91 (t, J = 1.1 Hz, IH), 4.83 (d, J = 6.4 Hz, 2H), 4.73 (dd, J = 7.5, 1.6 Hz, 4H), 3.62 - 3.54 (m, IH), 2.94 (s, 2H), 1.52 (s, 6H). LCMS m/z 429.32 [M+H]'.
310	z o t A/y z ' vi5\ )=( Γ /? z \ A-z IZ p 'z	FF As for compound 306	*H NMR (400 MHz, Methanol-^) δ 8.50 8.42 (m, 2H), 8.15 (d, J = 8.4, 2H), 7.97 (d, J = 1.1 Hz, 1 H), 7.65 - 7.59 (m, 2H), 7.37 (d, J = 1.2 Hz, IH), 7.10 - 7.02 (m, 2H), 6.98 (t, J = 1.1 Hz, IH), 5.87 (s, 2H), 2.87 (s, 2H), 1.46 (s, 6H). LCMS m/z 450.28 [M+H]'.
311	HO, yo FS H [ ήΧ Γη	As for compound 306	lH NMR (400 MHz, MethanolF) δ 8.62 (m, IH), 8.30 (m, IH), 8.16 (d, J = 8.3 Hz, 2H), 7.98 (s, IH), 7.85 (m, IH), 7.76 (m, IH), 7.63 (d, J = 8.2 Hz, 2H), 7.44 (s, IH), 7.00 (s, IH), 6.01 (s, 2H), 2.90 (s, 2H), 1.48 (s, 6H). LCMS m/z 450.29 [M+H]'.

507

Compound	Structure	Aldéhyde or ketone reagent/Method	'HNMR; LCMS m/z [M+H]
3121	H N- V	° O -z	See table footnote	*H NMR (400 MHz, MethanolA) Ô 8.17 8.09 (m, 2H), 7.98 (d, J = 1.1 Hz, IH), 7.77 - 7.68 (m, 2H), 7.40 (d, J = 1.1 Hz, IH), 7.33 (t, .1 = l.l Hz, IH), 7.27 (m, IH), 7.20 (m, IH), 6.97 (td, J = 7.5, 1.2 Hz, IH), 6.46 - 6.35 (m, IH), 5.52 (s, 2H), 3.21 (s, 2H), 2.49 2.34 (m, 2H), 2.19 2.02 (m, 3H), 1.71 (m, IH). LCMS m/z 479.35 [M+H]'.
313	H tA o	CL y-oH o X—ΞΝ W^F	Jl 0 As for compound 306	'H NMR (300 MHz, DMSOA) δ 12.99 (s, IH), 12.40 (s, IH), 8.13 - 7.99 (m, 2H), 7.90 (d, J = 1.0 Hz, IH), 7.62 - 7.51 (m, 2H), 7.43 - 7.27 (m, 2H), 7.27 - 7.12 (m, 3H), 6.84 - 6.68 (m, IH), 6.40 - 6.23 (m, IH), 3.15 - 2.94 (m, 2H), 2.13 - 1.99 (m, 3H), 1.46 (d, J = 12.6 Hz, 6H). LCMS m/z 481.34 [M+H]+.
314	H A	Z II	u 0 As for compound 306	'H NMR (300 MHz, DMSOA) δ 13.02 (s, IH), 12.39 (s, IH), 8.11 - 8.01 (m, 2H), 7.87 (d, J = 1.0 Hz, IH), 7.66 - 7.52 (m, 2H), 7.45 - 7.34 (m, 2H), 7.34 - 7.22 (m, 3H), 6.93 (d, J = 1.1 Hz, IH), 6.78 - 6.71 (m, IH), 6.30 - 6.16 (m, IH), 3.21 - 2.98 (m, 2H), 2.00 (d, J = 6.6 Hz, 3H), 1.47 (d, J = 2.1 Hz, 6H). LCMS m/z 463.26 [M+H]\ _________

508

Compound	Structure	Aldéhyde or ketone reagent/Method	‘H NMR; LC/WSz«/z[M+H]+
315	H Ό	AA II z	Larock indole method with CI882	JH NMR (400 MHz, Methanol-<74) δ 8.68 (d, J = 1.8 Hz, IH), 8.01 (s, IH), 7.93 7.84 (m, IH), 7.52 (dd, J = 8.1, 1.2 Hz, IH), 7.39 (d, J = 1.2 Hz, IH), 7.26 (td, J = 7.7, 1.6 Hz, IH), 7.09 (td, J = 7.6, 1.2 Hz, IH), 6.97 (d, J = 1.2 Hz, IH), 6.35 (d, J = 7.9 Hz, IH), 5.81 (s, 2H), 2.86 (s, 2H), 2.79 (m, 3H), 2.00 1.91 (m, 6H), 1.44 (s, 6H). LCMS m/z 530.29 [M+H]+.
316	H O	0 Il n-a // y AAV ν^-Ν N-= N A A/F	Larock indole method with C1883	‘H NMR (400 MHz, Methanol-J^) δ 8.72 8.64 (m, IH), 8.00 (d, J = 1.1 Hz, IH), 7.88 (m, IH), 7.43 (d, J = 1.2 Hz, IH), 7.35 7.25 (m, IH), 7.21 (m, IH), 7.01 - 6.89 (m, 2H), 6.43 - 6.34 (m, IH), 5.84 (s, 2H), 2.90 (s, 2H), 2.83 2.75 (m, 3H), 1.95 (dd, J = 13.5, 6.9 Hz, 6H), 1.45 (s, 6H). LCMS m/z 514.3 [M+H] λ
317	H N VL	HO y° A AlA —=n	As for compound 306	‘H NMR (400 MHz, Methanol-i74) δ 8.16 8.05 (m, 3H), 7.99 (d, J = 1.2 Hz, IH), 7.57 - 7.45 (m, 2H), 6.84 (t, J = 1.1 Hz, IH), 4.64 - 4.42 (m, IH), 2.92 (s, 2H), 2.75 (q, J = 12.2 Hz, 2H), 2.09 - 2.01 (m, 2H), 1.95 (d, J = 13.0 Hz, 2H), 1.85 (d, J = 9.4 Hz, IH), 1.59 (dd, J = 23.4, 9.2 Hz, 3H), 1.52 (s, 6H). LCMS

509

Compound	Structure	Aldéhyde or ketone reagent/Method	lH NMR; LCMS m/z [M+Hf
			m/z 441.29 [M+Hf.
318	H>° A H / 1 ÛAAA AA —=N	0 As for compound 306	‘H NMR (400 MHz, MethanolA) δ 8.13 8.09 (m, 2H), 8.08 (d, J = 1.0 Hz, IH), 7.72 (d, J = 1.1 Hz, IH), 7.58 - 7.49 (m, 2H), 6.92 (t, J = 1.1 Hz, IH), 4.31 (d, J = 7.6 Hz, 2H), 2.89 (s, 2H), 2.17 (m, IH), 1.83 1.60 (m, 3H), 1.52 (m, 8H), 1.18 (m, 5H). LCMS m/z 455.29 [M+Hf.
319	Οχ Aoh o H / nXIH A Aci A	AT CGo As for compound 306	'H NMR (400 MHz, MethanolA) δ 8.29 (dd, J = 4.8, 1.9 Hz, IH), 8.18 - 8.11 (m, 2H), 7.99 (d, J = 1.1 Hz, IH), 7.65 - 7.57 (m, 2H), 7.37 (d, J = 1.2 Hz, IH), 7.20 (dd, J = 7.7, 4.8 Hz, IH), 6.99 (t, J = 1.1 Hz, IH), 6.76 (dd, J = 7.7, 1.8 Hz, IH), 5.78 (s, 2H), 2.85 (s, 2H), 1.46 (s, 6H). LCMS m/z 484.15 [M+Hf.

Prepared by Larock indole cyclization between 6-bromo-N-[(2-fluorophenyl)methyl]-l Hindazol-5-amine and methyl 4-[2-[l-(cyanomethyl)cyclobutyl]ethynyl]benzoate Cl96. 2

6-bromo-N-[(2-chlorophenyl)methyl]-l-tetrahydropyran-2-yl-indazol-5-amine.

³' 6-bromo-N-[(2-fluorophenyl)m ethyl] -1 -tetrahydropyran-2-yl-indazol-5-amine.

510

Compound 320

4-[6-[l-(cyanomethyl)cyclobiityl]-5-(4-fluoro-3-methyl-phenyl)-lH-pyrrolo[2,3-f]mdazol-7yl]benzoic acid (320)

Compound 320 was prepared from C195 and alkyne C196 according to the method described for the préparation of compound 125. C195 was prepared from C116 and l-fluoro-4iodo-2-methyl-benzene to afford 4-[6-[l-(cyanomethyl) cyclobutyl ]-5-(4-fluoro-3-methyl phenyl)-lH-pyrrolo[2,3-f]indazol-7-yl]benzoic acid.

’H NMR (300 MHz, DMSO-A) § 12.99 (s, IH), 12.61 (s, IH), 8.09 - 8.03 (m, 2H), 8.03 7.97 (m, IH), 7.79 - 7.69 (m, 2H), 7.61 - 7.53 (m, IH), 7.51 - 7.44 (m, IH), 7.40 (t, J = 8.9 Hz, IH), 7.28-7.21 (m, IH), 6.99 (d, J = 1.1 Hz, IH), 3.19 (s, 2H), 2.39 - 2.32 (m, 3H), 2.32-2.2 (m, 2H), 2.02 - 1.88 (m, IH), 1.61 - 1.45 (m, 3H). LCMS m/z 479.28 [M+H]\

511

Compound 321 4-(5-(4-fluorophenyl-l,2,3,4,5,6-I3C6)-6-(tetrahydro-2H-pyran-4-yl)-l,5dihydropyrrolo[2,3-f] indazol- 7-yl)benzoic-2,3,5,6-d₄ acid (321)

Compound 321 was prepared from C2 using 4-fluoro-2Z3,3Z3,5À3_}6X3-benzenamine-^i:ïC₆ and (4~(ethoxy^carbonyl)phenyl-2,3,5,6-d4)boronic acid using the procedures described for the préparation of compound S4 and compound 33. ^!H NMR (300 MHz, DMSOA) S 12.99 (s, IH), 12.60 (s, IH), 8.00 (d, J = 1.0 Hz, IH), 7.97 - 7.72 (m, 2H), 7.44 - 7.30 (m, IH), 7.30 - 7.18 (m, 2H), 7.07 (d, J = 1.1 Hz, IH), 3.73 (d, J = 11.1 Hz, 2H), 3.17 - 2.95 (m, 3H), 1.72 - 1.61 (m, 4H).

LCMS m/z 466.37 [M+H]⁺.

512

Compound322

4-[6-(2-cyano-l, l-dimethyl-ethyl)-5-(4-fluorophenyl)-lH-pyn-olo[2,3-f] benzotriazol- 7yl]benzoic acid (322)

Step 1. Synthesis of 6-bromo-N-(4-fluoropheny!)-IH-benzotriazol-5-amine (C199)

Josiphos Pd G3 and Pd(dppf)Cl₂ (185 mg, 0,2002 mmol) was added to a degassed solution of 5,6-dibromo-lH-benzotriazole (557 mg, 2.011 mmol), 4-fluoroaniline (231 pL, 2,407 mmol), and sodium t-butoxide (590 mg, 6.14 mmol) in tetrahydrofuran (11 mL). A nitrogen atmosphère was maintained through the set-up and the vial sealed. The reaction mixture was stirred under a nitrogen atmosphère at room température ovemight. The mixture was diluted with ethyl acetate and washed with water. The organics were absorbed onto Celite® and purified on a 40 g Si gold cartridge. Purification by silica gel chromatography (Gradient: 0-100 % EtOAc in heptane) yielded 6-bromo-N-(4-fluorophenyl)~lH-benzotriazol-5-amine (338 mg, 54 %). ^lH NMR (300 MHz, DMSOA) δ 15,35 (s, IH), 8.32 (s, IH), 7.63 (s, IH), 7.29 - 7.07 (m, 5H). LCMS m/z 307.0 [M+Hf.

Step 2-3. Synthesis of 4-]6-(2-cyano-l,l-dimethyl-ethyl)-5-(4-fluorophenyl)-lH-pyrrolo[2,3f]benzotriazol-7-yl]benzoic acid (322)

Compound 322 was prepared in two steps from C199 using the method described for the préparation of compound 125. Purification by reversed-phase chromatography (Column: Cl 8. Gradient: 10-100 % MeCN in water with 0.1 % formic acid) afforded the desired product, 513

Concentrated the desired fractions to dryness under reduced pressure to give 4-[6-(2-cyano-l,ldimethyl-ethyl)-5-(4-fluorophenyl)-lH-pyrrolo[2,3-f]benzotriazol-7-yl]benzoic acid (Trifluoroacetic Acid (0.5)) (18.7 mg, 58 %). ’H NMR (300 MHz, DMSOA) δ 15.42-15.00 (bs, IH), 13.09 (s, IH), 8.17 - 8.09 (m, 2H), 7.76 - 7.62 (m, 4H), 7.62 - 7.50 (m, 2H), 7.34-6.73 (m, 2H), 2.64 (s, 2H), 1.25 (s, 6H). LCMS m/z 454.3 [M+H]⁺.

Compound 323

4-[6-(2-cyano-I,1 -dimethyl-ethyif7-(4-fluorophenyl)-IH-pyrrolo[3,2-fj indazol-5-yl] benzoic acid (323)

tBuXPhos Pd G3 NaOtBu

Synthesis of 4-[6-(2-cyano-f l-dimethyl-ethyl)-7-(4-fluorophenyl)-lH-pyrrolo[3,2-f]indazol-5yl] benzoic acid (323)

Compound 323 was prepared from compound C204 using the method described for the préparation of compound 324. In this example, the addition of tosyl protecting group was omited. 4-[6-(2-cyano-l, 1 -dimethyl-ethyI)-7-(4-f!uorophenyl)-1 H-pyrrolo[3,2-f]indazol-5yl]benzoic acid (29.5 mg, 67 %) . 'H NMR (300 MHz, DMSOA) δ 13.06 (s, IH), 12.49 (s, IH), 8.12 - 8.05 (m, 2H), 8.00 (d, J = 1.0 Hz, IH), 7.70 - 7.49 (m, 6H), 7.25 (d, J = 1.1 Hz, IH), 6.50 (t,J= 1.2 Hz, 1 H), 2.62 (s, 2H), 1.24 (s, 6H). LCMS m/z 453.31 [M+H] ^h.

514

Compound 324

4-[6-(2-cyano-l, 1 -dimethyl-ethyl)- 7-(4-fluorophenyl)-lH-pyrrolo[3,2-f] indazol-5-yl] benzoic acid (324)

2. NaOH

Step 1. Synthesis of 6-bromo-N-(4-fluorophenyl)~FH-benzimidazolS-amine (C202)

Compound 202 was prepared by amination of C201 using tBuXPhosPd G3, using the method described for the préparation of compound C199. Purification by silica gel chromatography (Gradient: 0-100 % EtOAc in heptane) yielded 6-bromo-N-(4-fluorophenyl)10 lEI-benzimidazol-5-amine (270 mg, 39 %). LCMS m/z 306.01 [M+H]⁺.

Step 2. Synthesis of l-(benzenesulfonyl)-6-bromo-N-(4~fltiorophenyl)benzimidazol-5-amine (C203)

Compound 203 was prepared from C202 using the method described for the préparation of compound C5 from C4. Purified on a Si 40 g gold cartridge and eluted with 0-100 % ethyl 15 acetate in heptane to give a mixture of N-l and N-2 indazole protected desired product, 1(benzenesulfonyl)-6-bromo-N-(4-fluorophenyl)benzimidazol-5-amine (100 mg, 41 %). LCMS m/z 446.11 [M+H]⁺.

Step 3. Synthesis of methyl 4-[l-(benzenesidfonyl)-6-(2-cyano-l,l-dimethyl-ethyl)-5-(4fluorophenyl)pyrrolo[2,3-f]benzimidazol-7-yl]benzoate (323)

515

Compound 324 was prepared from C203 and C147 using the method described for the préparation of compound 125. 4-[6-(2-cyano-l,l-dimethyl-ethyl)-5-(4-fluorophenyl)-lHpyrrolo[2,3-f]benzimidazol-7-yl]benzoic acid (8.5 mg, 20 %). ’H NMR (300 MHz, DMSO-î/₆) Ô 12.10 (s, 2H), 8.11 (s, IH), 8.11 - 8.05 (m, 2H), 7.69-7.58 (m, 4H), 7.58 -7.46 (m, 2H), 6.99 (s, 5 IH), 6.66(s, IH), 2.62 (s, 2H), 1.24 (s, 6H). LCMS m/z 453.22 [M+H]⁴.

Compound 325

4-[4-(4-fluorophenyl)-5-(2-methoxy-l, 1 -dimethyl-ethyl)-2,4,10,1110 tetrazatricyclo[7.3.0.03,7]dodeca-1,3(7),5,8,1 l-pentaen-6-yl]benzoic acid (325)

Step 1. Synthesis of 3-bromo-N-(4fluorophenyl)-6-methyl-5-mtro~pyridin-2-amine (C207)

A 100 mL round bottom flask was charged with 3-bromo-2-chloro-6-methyl-5-nitropyridine (2.69 g, 10.70 mmol) and DMSO (22 mL) was added. 4-Fluoroaniline (3 mL, 31.67 mmol) was added and the reaction was heated to 120 °C. After 30 minutes, The reaction

516 mixture was allowed to cool to room température, and was poured into water (500 mL), forming a green precipitate. This precipitate was collected by vacuum fdtration and washed with excess water. The crude material was purified by column chromatography using an 80 g silica gel gold column with 0-20 % EtOAc in Heptane as eluent. The desired product was obtained as a mustard yellow solid. 3-bromo-N-(4-fluorophenyI)-6-rnethyl-5-nitro-pyridin-2-amine (3.1888 g, 89 %). ^lH NMR (400 MHz, DMSO-J) δ 9.14 (s, IH), 8.56 (s, IH), 7.66 (ddd, J = 9.1, 5.0, 1.7 Hz, 2H), 7.21 (td, J = 8.8, 1.7 Hz, 2H), 2.61 (s, 3H). LCMS m/z 325.9 [M+H]*.

Step 2. Synthesis of methyl 4-[l-(4-fluorophenyl)-2-(2-methoxy-l,l-dimethyl-ethyl)-6-methyl-5nitro-pyrrolo[2,3-b]pyridin-3-yl] benzoate (C209)

Compound C209 was prepared from C207 and C208 using Larock indole cyclization as described for the préparation of compound 125. Methyl 4-[l-(4-fluorophenyl)-2-(2-methoxy-l,ldimethyl-ethyl)-6-methyl-5-nitro-pyrrolo[2,3-b]pyridin-3-yl]benzoate (369.2 mg, 51 %). 'H NMR (4Û0 MHz, Chloroform-t/) δ 8.17 (d, J = 7.8 Hz, 2H), 8.09 (s, IH), 7.54 (d, J = 7.7 Hz, 2H), 7.48 - 7.41 (m, 2H), 7.30 - 7.25 (m, 2H), 4.01 (s, 3H), 3.08 (s, 3H), 3.04 (s, 2H), 2.77 (s, 3H), 1.16 (s, 6H). LCMS m/z 492.15 [M+H]⁺.

Step 3. Synthesis of methyl 4-[5-amino-l-(4-fluorophenyl)-2-(2-methoxy-1,1 -dimethyl-eth.yl)-6methyl-pyrrolo[2,3-b]pyridin-3-yl] benzoate (C210)

A 0.5-2 mL microwave vial was charged with methyl 4-[l-(4-fluorophenyl)-2-(2methoxy-1,1 -dimethyl-ethyl)-6-inethyl-5-nitro-pyrrolo[2,3-b]pyridin-3-yl]benzoate C209 (30 mg, 0.06057 mmol), NH4CI (18 mg, 0.3365 mmol), and iron (21 mg, 0.3760 mmol). MeOH (250 pL) was added and the reaction was heated to 80 °C over the weekend. Upon returning, ail starting material had been consumed. Water (5 mL) and dichloromethane (5 mL) were added, and the mixture was passed through a phase separator. The solvent was evaporated and the crude material was taken up in minimal DMSO and purified by reverse phase chromatography using a gradient of 10-100 % acetonitrile in water with 0.2 % formic acid on a 15.5 g gold C18 column. The desired product was obtained as a white solid. Methyl 4-[5-amino-l-(4fluorophenyl)-2-(2-methoxy-l,l-dimethyl-ethyl)-6-methyl-pyrrolo[2,3-b]pyrîdin-3-yl]benzoate (13.0 mg, 41 %). ’H NMR (400 MHz, Chloroformé) δ 8.12 (dd, J = 8.0, 1.7 Hz, 2H), 7.57 7.49 (m, 2H), 7.45 (dt, J = 6.6, 3.4 Hz, 2H), 7.23 (t, J = 8.1 Hz, 2H), 6.72 (s, IH), 3.99 (s, 3H), 3.07 (s, 3H), 3.03 (s, 2H), 2.39 (s, 3H), 1.12 (s, 6H). LCMS m/z 462.14 [M+H]⁺.

4-[4-(4-fluorophenyl)-5-(2-methoxy-l,l-dimethyl-ethyl)-2,4,10,lltetrazatricyclo[7,3.0.03,7]dodeca-l,3(7),5,8,1 l-pentaen-6~yl]benzoic acid (325)

517

A 1-drain vial was charged with methyl 4-[5-amino-l-(4-fluorophenyl)-2-(2-methoxy-l,ldîmethyl-ethyl)-6-methyl-pyrrolo[2,3-b]pyridin-3-yl]benzoate ( 13 mg, 0.02481 mmol) and KOAc (3 mg, 0.03057 mmol). Chloroform (250 pL) was added and the mixture was stirred at 65 °C for 30 minutes. Then, acetic anhydride (7 pL, 0.07419 mmol) was added dropwise, followed by isoamyl nitrite (4 pL). The mixture was allowed to stir for 3 h. 1,4,7,10,13,16hexaoxacyclooctadecane (1 mg, 0.003783 mmol) was added and the mixture stirred overnight at 65 °C. The reaction mixture was washed with water (5 mL) and passed through a phase separator. The organic phase was collected and the solvent was evaporated. The crude material was taken up in THF (240 pL) and MeOH (120 pL), and NaOH (149 pL of I M, 0.1490 mmol) was added. The reaction was heated to 50 °C. After 30 minutes, the reaction was complété by LCMS. The solvent was evaporated and the crude material was taken up in minimal water. HCl (149 pL of 1 M, 0.1490 mmol) was added, forming a precipitate. The solvent was evaporated and the crude material was taken up in minimal DMSO. Purification by reverse phase chromatography using a gradient of 10-100 % acetonitrile in water with 0.2 % formic acid on a 15.5 g gold C18 column afforded the desired product was obtaîned as an off-white solid. 4-[4(4-fluorophenyl)-5-(2~methoxy-l,l-dîmethyl-ethyl)-2,4,10J l-tetrazatricyclo[7.3.0.03,7]dodeca1,3(7),5,8,1 l-pentaen-6-yl]benzoic acid (3.3 mg, 26 %).’H NMR (400 MHz, Methanol</_#) δ 8.15 (d, J = 7.6 Hz, 2H), 8.02 (s, IH), 7.59 (d, J = 7.6 Hz, 2H), 7.54 (dt, J = 9.3, 3.2 Hz, 2H), 7.45 (s, IH), 7.37 (t, J = 8.2 Hz, 2H), 3.11 -3.02 (m, 5H), 1.19 (s, 6H). LCMS m/z 459.12 [M+H]⁺.

518

Compound 326

4-[4-(4-fluorophenyl)-5-tetrahydropyran-4-yl-2,4,10,1 l-tetrazatricyclo[7.3.0.03,7]dodeca1,3(7),5,8,11 -pentaen-6-yl] benzoic acid (326)

Step 1. N-(4-fluorophenyl)-6-methyl-5-nitro-3-(2-tetrahydropyran-4-ylethynyl)pyridin-2-amine (C211)

Compound 211 was prepared from C207 by Sonagashira coupling according to the method described for préparation of C2. N-(4-fluorophenyl)-6-methyl-5-nitro-3-(210 tetrahydiOpyran-4-ylethynyl)pyridin-2-amine (1.0132 g, 65 %). ^!H NMR (400 MHz, DMSOA) δ 8.90 (s, IH), 8.27 (s, IH), 7.68 (dd, J = 8.7, 5.1 Hz, 2H), 7.26 - 7.15 (m, 2H), 3.83 (dt, J = H.3, 4.2 Hz, 2H), 3.46 (t, J = 10.6 Hz, 2H), 3.05 - 2.94 (m, lH), 2.65 (s, 3H), 1.95 - 1.85 (m, 2H), 1.79 - 1.62 (m, 2H). LCMS m/z 356.04 [M+H]⁺.

Step 2. Synthesis of l-(4-fluorophenyl)-6-methyl-5-nitro-2-tetrahydropyran-4-yl~pyrrolo[2,315 b]pyridine (C212)

A 100 mL round bottom flask was charged with N-(4-fluorophenyl)-6-methyl-5-nitro-3(2-tetrahydropyran-4-ylethynyl)pyridin-2-amine (957 mg, 2.649 mmol) and PdCL (160 mg,

519

0.9023 mmol). MeCN (31 mL) was added, and the reaction was heated to 50 °C. After 24 h, the reaction was complété by LCMS. The solvent was evaporated, and the crude material was purified by column chromatography using a 40 g silica gel gold column with 0-30 % EtOAc in Heptane as eluent. The product was obtained as a light orange solid. l-(4-fluorophenyl)-65 methyl-5-nitro-2-tetrahydropyran-4-yl-pyrrolo[2,3-b]pyridine (534.4 mg, 54%). ‘H NMR (400 MHz, DMSOA) δ 8.72 (s, IH), 7.60- 7.53 (m, 2H), 7.45 (td, J = 8.6, 1.7 Hz, 2H), 6.68 (s, IH), 3.84 (d, J = 11.2 Hz, 2H), 3.28-3.17 (m, 2H), 2.85 (p, J = 7.7 Hz, IH), 2.68 (s, 3H), 1.78- 1.58 (m,4H). LCMS m/z 356.04 [M+Hf.

Step 3. Synthesis of l-(4-fluorophenyl)-6-methyl-2-tetrahydropyran-4-yl-pyrrolo[2,3-b]pyridin10 5-amine (C213)

A 10-20 mL microwave vial was charged with l~(4-fluorophenyl)-6-methyl-5-nitro-2tetrahydropyran-4-yl-pyrrolo[2,3-b]pyridine (530 mg, 1.423 mmol), NH₄C1 (1030 mg, 19.26 mmol), and iron (850 mg, 15.22 mmol). MeOH (8 mL) was added and the reaction was heated to 80 °C over 36 h. The reaction was filtered, and the sohd washed with excess MeOH and 15 CH2CI2. The filtrate was evaporated, and the crude material was taken up in minimal DMSO and purified by reverse phase chromatography using a gradient of 10-100 % acetonitrile in water with 0.2 % fonnic acid on a 50 g gold Cl 8 column. The desired product was obtained as a light brown solid. 1 -(4-fluorophenyI)-6-methyl-2-tetrahydropyran-4-yl-pyrrolo[2,3-b]pyridin-5amine (125.5 mg, 24 %). LCMS m/z 326.08 [M+H]⁺.

Step 4. Synthesis of l-[4-(4-fluorophenyl)-5-tetrahydropyran-4-yl-2,4,10,11tetrazatricyclo[7.3.0.03,7]dodeca-l(9),2,5,7,1 l-pentaen-10-yl]ethenone (C214)

I-(4-fluorophenyl)-6-methyl-2-tetrahydropyran-4-yl-pyrrolo[2,3-b]pyridin-5-amine (125 mg, 0.3842 mmol), KOAc (116 mg, 1.182 mmol), and 1,4,7,10,13,16-hexaoxacyclooctadecane (217 mg, 0.8210 mmol). chloroform (5 mL) was added, followed by acetic anhydride (110 pL, 25 1.166 mmol) and isoamyl nitrite (110 pL, 0.8188 mmol). The reaction was heated to 60 °C.

After 6 days, the solution was washed with sat. NaHCO₃, and the mixture was passed through a phase separator. The organic phase was collected, and the solvent was evaporated. The crude material was purified by column chromatography using a 24 g silica gel gold column with 040 % EtOAc in Heptane as eluent. The desired product was obtained as a light yellow solid. 130 [4-(4-fluorophenyl)-5-tetrahydropyran~4-yl-2,4,l 0,1 l-tetrazatricyclo[7.3,0.03,7]dodeca1(9),2,5,7,1 l-pentaen-10-yl]ethanone (26.3 mg, 18%). ‘H NMR (400 MHz, DMSOA) δ 8.81 (d, J = 0.8 Hz, IH), 8.56 (d, J = 0.8 Hz, IH), 7.63 - 7.55 (m, 2H), 7.51 - 7.43 (m, 2H), 6.77 (d, J = 0.8 Hz, IH), 3.90 - 3.79 (m, 2H), 3.29 - 3.21 (m, 2H), 3.00 - 2.86 (m, IH), 2.74 (s, 3H), 1.76 1.66 (m,4H). LCMS m/z 379.03 [M+H] ’.

520

Step 5. Synthesis of 4-[4-(4-fluorophenyl)~5-tetrahydropyran-4-yl-2,4,10,lItetrazairicyclo[73.0.03.7]dodeca-l,3(7),5,8,1 l-pentaen-6-yl]benzoïc acid (326)

A 20 mL scintillation vial was charged with l-[4-(4-fluorophenyl)-5-tetrahydropyran-4yl-2,4,10,11-tetrazatricyclo[7.3.0.03,7]dodeca-l (9),2,5,7,1 l-pentaen-10-yl]ethanone (25 mg, 0.06607 mmol) and NIS (45 mg, 0.2000 mmol). DCM (2000 pL) was added, and the reaction was stirred at room temperature. The solvent was evaporated, and the crude material was purified by column chromatography using a 12 g silica gel gold column with 0-40 % EtOAc in Heptane as eluent. The product C215 was used in the subséquent step without further purification.

A 0.5-2 mL microwave vial was charged with 1 -[4-(4-fluorophenyl)-6-iodo-5tetrahydropyran-4-yl-2,4,10,l l-tetrazatricyclo[7.3.0.03,7]dodeca-l(9),2,5,7,l l-pentaen-10yl]ethenone, (4-ethoxycarbonylphenyl)boronic acid (30 mg, 0.1546 mmol), and K₃PO₄ (65 mg, 0.3062 mmol). dioxane (250 pL) and water (50 pL) were added, and the solution was degassed with N₂ for 10 minutes. Then, XPhos Pd Gl (5 mg, 0.0064 mmol) was added, and the reaction was heated to 80 °C. After 2.5 h, water (5 mL) and dichloromethane (5 mL) were added, and the mixture was passed through a phase separator. The organic phase was collected, and the solvent was evaporated. The crude material was directly subjected to the next reaction.

A 20 mL scintillation vial was charged with the crude reaction mixture and dissolved in THF (1000 pL) and MeOH (500 pL). NaOH (396 pL of I M, 0.3960 mmol) was added and the reaction was heated to 50 °C. After 30 minutes, the reaction was complété by LCMS. The solvent was evaporated, and the crude material was taken up in minimal water. HCl(396 pLof 1 M, 0.3960 mmol) was added, forming a precipitate. The solvent was evaporated, and the crude material was taken up în minimal DMSO and purified by reverse phase chromatography using a gradient of 10-100 % acetonitrile în water with 0.2 % formic acid modifier on a 15.5 g gold CI8 column. The desired product was obtained as a white solid. 4-[4-(4-fluorophenyl)-5tetrahydropyran-4-yl-2,4,10,l l-tetrazatricycio[7.3.0.03,7]dodeca-l,3(7),5,8,l l-pentaen-6yl]benzoic acid (2.5 mg, 8 %). LCMS m/z 457.1 [M+H]'.

521

Compound 327

4-[I0-(4-fliiorophenyl)-ll-(2-methoxy-l,l-dimethyl-eihy/)-2,4,5,10tetrazatricyclo[7.3.0.03, 7]dodeca-l,3(7),5,8,ll-pentaen-12-yl]benzoic acid (327)

Compound 327 was prepared from C218 using the method described for the préparation of compound 125. ^lH NMR (400 MHz, MethanolA) δ 8.14 (d, J = 7.7 Hz, 2H), 8.00 (s, IH), 7.65 7.52 (m, 4H), 7.43 - 7.34 (m, 3H), 3.39 - 3.27 (m, 5H), 1.20 (s, 6H). LCMS m/z 459.12 [M+H]⁺.

522

Compound 328

4-[10-(4-fluorophenyl)-ll-tetrahydropyran-4-yl-2,4,5,10-letrazatricyclo[7.3.0.03,7]dodeca1,3(7),5,8, ll-pentaen-12-yl]benzoic acid (328)

tBuCOCI KOtBu

K₃PO₄

XPhos PdG1

1. NaOH 2. HCl

Compound 328 was prepared from C217 using the method described for the préparation of compound 108. ^!H NMR (400 MHz, DMSO-A) Ô 13.14 (s, IH), 12.97 (s, IH), 8.06 (d, J = 8.4 Hz, 3H), 7.68 (dd, J = 8.5, 4.9 Hz, 4H), 7.57 (s, IH), 7.53 (t, J = 8.5 Hz, 2H), 3.74 (d, J = 11.2 Hz, 2H), 3.18-3.04 (m, 3H), 1.77 - 1.65 (m, 4H). LCMS m/z 457.1 [M+H]⁺.

523

Compound 329

4-[10-(4-fluorophenyl)-l l-isopropyl-2,4,5,8,10-pentazatricyclo[7.3.0.03,7]dodeca-

pTSA

1,3(7),5,8,1I-pentaen-12-yl]benzoic acid (329)

0224 cfjoc C226

1.K₃PO₄, tBuCOCI KOtBu

2. MIS

C229

Step 1. Synthesis of 5-bromo-l-tetrahydropyran-2-yl-pyrazolo[3,4-b]pyrazine (C225)

To a solution of 5-bromo-lH-pyrazolo[3,4-b]pyrazine (1.315 g, 6.6OS mmol) and 3,4dihydro-2H-pyran (1.8 mL, 19.73 mmol) in dichloromethane (22 mL) was added p-TsOH (Water (1)) (126 mg, 0.6624 mmol).

The reaction was stirred ovemight at room température and was quenched with a 10 saturated solution of sodium bicarbonate. The phases were separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic layers were dried over Na₂SO4, filtered and evaporated. Purification by silica gel cartridge (40 g column) eluting with EtOAc/Heptane 100:0 to 50:50 gave 5-bromo-l-tetrahydropyran-2-yl-pyrazolo[3,4-b]pyrazine (1.67 g, 87 %) . 'H NMR (400 MHz, Chloroform-d) δ 8.55 (s, IH), 8.26 (s, IH), 6.02 (dd, J =

524

10.3 , 2.6 Hz, IH), 4.15 - 4.06 (m, IH), 3.85 - 3.74 (m, IH), 2.72 - 2.60 (m, IH), 2.21 - 2.15 (m, 1 H), 2.05 - 1.96 (m, 1 H), 1.85 - 1.75 (m, 2H), 1.69 - 1.64 (m, 1 H). LCMS m/z 296.25 [M+H] \ Step 2: Synthesis of 5-bromo-6-(3-methylbut-1 -ynyl)-1 -tetrahydropyran-2-yl-4,7dihydropyrazolo]3,4-b]pyrazîne (C226)

5-bromo-6-(3-methylbut-l-ynyI)-l-tetrahydropyran-2-yl-pyrazolo[3,4-b]pyrazine

At rt, to a solution of 3-methylbut-l-yne (72 mg, 1.057 mmol) in THF (1.0 mL) was slowly added chloro(isopropyl)magnesium chlorolithium (598 pL of 1.3 M, 0.7774 mmol). After stirring the mixture for 15 min, the reaction was heated at 40 °C for 45 min and cooled down to 78 °C. A solution of 5-bromo-l-tetrahydropyran-2-yl-pyrazolo[3,4-b]pyrazine (100 mg, 0.3532 mmol) în THF (LO mL) was added dropwise. The reaction was stirred 30 min at -78 °C, then warmed up to 0 °C, stirred for 30 min. The mixture was wanned to room température, stirred I h, then heated at 65 °C for 45 min. The product was using immédiate!y in the subséquent reaction. 5-bromo-6-(3-methylbut-l-ynyl)-l-tetrahydropyran-2-yl-4,7-dihydropyrazolo[3,4b]pyrazine (124 mg, 80 %) LCMS m/z 351.05 [M+H]⁺.

Steps 3-9. Synthesis of 4-[10-(4-fluorophenyl)-ll~isopropyl-2,4,5,8,10pentazatricyclo[7.3.0.03,7]dodeca-l,3(7),5,8,ll-pentaen-12-yl]benzoic acid (329)

Compound 329 was prepared from C226 as described for the préparation of S3 from C2, and then the préparation of compound 107. An additional step for the remove of the THP protecting group by treatment with HCl was performed. 4-[10-(4-fluorophenyl)-ll-isopropyl2,4,5,8,10-pentazatricyclo[7.3.0.03,7]dodeca-l,3(7),5,8,l l-pentaen-12-yl]benzoic acid (5.3 mg, 13 %) . ‘FI NMR (400 MHz, DMSOA) δ 13.61 (s, IH), 8.27 (s, IH), 8.08 (d, J = 8.4 Hz, 2H), 7.72 - 7.65 (m, 4H), 7.53 - 7.44 (m, 2H), 3.34 - 3.27 (overlap water peak, m, 1 FI), 1.17 (d, J = 7.1 Hz, 6H). LCMS m/z 416.15 [M+H]⁺.

Compound 330

4-[ 10-(4-fluorophenyl)-lI-tetrahydropyran-4-yl-2,4,5,10-tetrazatricyclo[7.3.0.03,7]dodeca1,3(7),5,8,ll-pentaen-12-ylj benzamide (330)

525

Compound 330 was prepared from compound 328 using the method described for the préparation of compound 128. *H NMR (400 MHz, Methanol A) δ 8.39 (s, IH), 8.20 (s, IH), 8.12 - 8.03 (m, 2H), 7.72 - 7.61 (m, 4H), 7.54 - 7.43 (m, 2H), 3.79 (dd, J = 11.3, 3.9 Hz, 2H), 3.19 (td, J = H.6, 2.6 Hz, 2H), 3.15 - 3.04 (m, IH), 1.86 - 1.65 (m, 4H). LCMS m/z 456.37 5 [M+H] 4

Compound 331

4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-1 H-pyrrolo[3,2-j]indazoi-7-yl]benzoic acid (331)

C234

526

Step 1. Synthesis of tert-butyl 4-[(5-chloro-l-tetrahydropyran-2-yl-indazol-6-yl)amino]benzoate (C231)

In a 30 mL microwave vial was loaded 6-bromo-5-chloro-l-tetrahydropyran-2-ylindazole (1 g, 3.169 mmol), tert-butyl 4-aminobenzoate (74S mg, 3.871 mmol), Pd₂(dba)₃, (142 mg, 0.1551 mmol), rac-BINAP (120 mg, 0.19 mmol) and Cs₂CO₃ (1.63 g, 5.03 mmol). tertbutyl 4-aminobenzoate (748 mg, 3.871 mmol) in THF (20 mL) was added. The mixture was bubbled with N₂. The vial was sealed and heated at 80 °C for 10 h. The mixture was cooled to rt, partitioned in EtOAc and water, extracted with EtOAc (3x). The organic phase was dried over Na₂SO₄, filtered and evaporated. Purification by silica gel chromatography (24 g silica gel, EtOAc/heptane 0-50 %) and then a second time (24 g silica gel, EtOAc/DCM 0-30 %) afforded the product.

tert-butyl 4-[(5-chloro-l-tetrahydropyran-2-yl-indazol-6-yl)amino]benzoate (948 mg, 70 %). ’H NMR (300 MHz, Chloroform-tf) δ 7.99 (d, J = 8.8 Hz, 2H), 7.91 (d, J = 0.9 Hz, IH), 7.78 (s, IH), 7.56 (t, J = 0.7 Hz, IH), 7.23 (d, J = 8.7 Hz, 2H), 6.46 (s, IH), 5.58 (dd, J = 9.2, 2.6 Hz, IH), 4.08 -3.89 (m, IH), 3.83 - 3.53 (m, 1 H), 2.52 (ddd, J = 13.3, 10.1, 6.8 Hz, IH), 2.24 - 2.07 (m, 2H), 1.82 - 1.60 (m, 3H), 1.62 (s, 9H). LCMS m/z 428.2 [M+H]⁺.

Step 2. Synthesis of tert-butyl 4-(l-tetrahydropyran-2-yl-6-telrahydropyran-4-yl-pyrrolo[3,2J]îndazol-7-yl)benzoate (C232)

In a 30 mL microwave tube was loaded PdCl₂(PhCN)₂ (42 mg, 0.1095 mmol), X-Phos (157 mg, 0.3293 mmol), Cs₂CO₃ (1.8 g, 5.525 mmol) and acetonitrile (5 mL). The mixture was bubbled with N₂. tert-butyl 4-[(5-chloro-l-tetrahydropyran-2-yl-indazol-6-yl)amino]benzoate (940 mg, 2.197 mmol) in acetonitrile (15 mL) was added. After 5 min, tert-butyl 4-[(5-chloro-ltetrahydropyran-2-yl-îndazoI-6-yl)amino]benzoate (940 mg, 2.197 mmol)in acetonitrile (4 mL) was added. The vial was sealed and heated at 80 °C for 3 h. The mixture was concentrated. The residue was suspended în water and S mL IN HCl was added. The mixture was extracted with DCM (3x). The organic phase was dried over Na₂SO₄, filtered and evaporated. Silica gel chromatography (40 g silica gel, EtOAc/heptane 0-50 %) afforded the product. tert-butyl 4-(ltetrahydropyran-2-yl-6-tetrahydropyran-4-yI-pyrrolo[3,2-f]indazol-7-yl)benzoate (448 mg, 37 %). *H NMR (300 MHz, Chloroform-ri) δ 8.25 (d, J = 8.7 Hz, 2H), 8.12 (d, J = 0.8 Hz, IH), 7.88 (d, J = 1.0 Hz, IH), 7.50 (d, J= 8.3 Hz, 2H), 7.03 (d, J = LO Hz, IH), 6.54 (d, J = 0.9 Hz, IH), 5.60 (dd, J = 9.2, 2.8 Hz, IH), 4.10-3.85 (m, 3H), 3.77 - 3.54 (m, 2H), 3.35 (tt, J = 11.6, 2.6 Hz, 2H), 2.87 (td, J = 11.2, 5.6 Hz, IH), 2.62 (m, IH), 2.26 - 1.73 (m, 8H), 1.6S (s, 9H). LCMS m/z 502.28 [M+H]⁺.

Step 3. Synthesis of tert-butyl 4-(6-tetrahydropyran-4-yl-IH-pyrrolo[3,2-f]indazol-7-yl)benzoate (C233)

527

To a solution of tert-butyl 4-(l-tetrahydropyran-2-yI-6-tetrahydropyran-4-yl-pyrrolo[3,2fjindazol-7-yl)benzoate (222 mg, 0.4049 mmol) in MeOH (10 mL) was added methanol (Hydrochloride sait) (3 mL of 1.25 M, 3.750 mmol) (HCl in MeOH). The mixture was in a sealed vial and stirred at 50 °C for 3 h. The mixture was cooled with dry ice, 2-methylpropan-2olate (Potassium Ion (1 )) (1.3 mL of 1 Μ, 1.300 mmol) was added to neutralized (pH ca 9). Tire mixture was evaporated. The residue was dissolved in DCM, brine was added. The mixture was extracted with DCM (3x). The organic phase was dried over Na₂SO₄, filtered and evaporated. Purification by silica gel chromatography (4 g silica gel, EtOAc/heptane 0-50 %) afforded the product. White solid. tert-butyl 4-(6-tetrahydropyran-4-yl-lH-pyrrolo[3,2-f]indazol-7yl)benzoate (131 mg, 67 %). 'H NMR (300 MHz, Chloroform-Jj δ 10.11 (s, IH), 8.23 (d, J = 8.4 Hz, 2H), 8.15 (d, J = 1.1 Hz, IH), 7.91 (d, J = 1.1 Hz, IH), 7.55-7.41 (m, 2H), 7.02 (q, J = LO Hz, IH), 6.55 (d, J = 0.8 Hz, IH), 3.99 (ddd, J = 11.6,4.2,2.0 Hz, 2H), 3.49- 3.26 (m, 2H), 2.89 (ddt, J = 15.3, 11.0, 4.2 Hz, IH), 1.94 - 1.70 (m, 4H), 1.67 (s, 9H). LCMS m/z 418.26 [M+H]⁺.

Step 4. Synthesis of tert-butyl 4-[ 1-(2,2-dimethylpropanoyl)-6-tetrahydropyran-4-yl-pyn-olo[3,ΙΑ indazol-7-yl] benzoate (C234)

A mixture of tert-butyl 4-(6-tetrahydropyran-4-yl-lH-pyrrolo[3,2-f]indazol-7yl)benzoate (50 mg, 0.1061 mmol) and 2,2-dimethylpropanoyl 2,2-dimethylpropanoate (2 mL, 9.858 mmol) was heated at 80 °C for 90 min. The mixture was evaporated in vacuum at 70 °C. The residue was suspended in aqueous sodium bicarbonate, extracted with DCM (3x). The organic phase was dried over Na₂SO₄, filtered and evaporated. Silica gel chromatography (2x4 g silica gel, 0-30%) afforded the product as a white solid. tert-butyl 4-[I-(2,2dimethy lpropanoyl)-6-tetrahydropyran-4-yl-pyrro!o[3,2-f| indazol-7-yl]benzoate (57 mg, 107 %). 'H NMR (300 MHz, Chloroform-if) δ 8.21 - 8.10 (m, 2H), 8.08 (d, J = 0.8 Hz, IH), 8.04 (d, J = 0.9 Hz, IH), 7.79 (d, J = 1.0 Hz, IH), 7.43 - 7.29 (m, 2H), 6.50 (d, J = 0.8 Hz, IH), 3.89 (dd, J = 10.8, 3.7 Hz, 2H), 3.26 (td, J = 11.6, 2.7 Hz, 2H), 2.88 - 2.72 (m, IH), 1.84 - 1.63 (m, 4H), 1.59 (s, 9H), 1.47 (s, 9H). LCMS m/z 502.3 [M+H]⁴.

Step 5. Synthesis of tert-butyl 4-[l-(2,2-dimethylpropanoyl)-5-iodo-6-tetrahydropyran-4-ylpyrrolo[3,2-f] indazol- 7-yl] benzoate (C235)

To a solution of tert-butyl 4-[l-(2,2-dimethylpropanoyl)-6-tetrahydropyran-4-ylpyrroIo[3,2-f]indazol-7-yl]benzoate (124 mg, 0.2472 mmol) in DCM (15 mL) was added NIS (115 mg, 0.5111 mmol), After 10 minutes, the reaction was complété by LCMS. After 30 min, the mixture was loaded onto 2 x4 g silica gel, and eluted with 0-30 % EtOAc in heptane as eluent. tert-butyl 4-[l -(2,2-dîmethylpropanoyl)-5-iodo-6-tetrahydropyran-4-yl-pyrrolo[3,2f]indazol-7-yl]benzoate (154 mg, 99 %). ^lH NMR (300 MHz, Chloroform-i/) δ 8.34 - 8.16 (m, 528

3H), 7.97 (d, J = 0.9 Hz, IH), 7.81 (d, J = 0.9 Hz, IH), 7.39 (d, J = 8.5 Hz, 2H), 4.03 (dd, J = 11.5, 4.2 Hz, 2H), 3.34 (td, J = 11.8, 1.8 Hz, 2H), 3.02 (tt, J = 12.4, 3.6 Hz, IH), 2.48 (qd, J = 12.6, 4.4 Hz, 2H), 1.69 (s, 9H), 1.65-1.57 (m, 2H), 1.55 (s, 9H). LCMS m/z 628.28 [M+H]⁺.

Step 6. Synthesis of tert-butyl 4-[l-(2,2-dimethylpropanoyl)-5-(4-fluorophenyl)-6tetrahydropyran-4-yl-pyrrolo [3,2-fJ indazol- 7-yl] benzoate

In a 30 mL microwave vial was charged with tert-butyl 4-[l-(2,2-dimethylpropanoyl)-5iodo-6-tetrahydropyran-4-yl-pyrrolo[3,2-f]indazol-7-yl]benzoate (63 mg, 0.1004 mmol), (4fluorophenyl)boronic acid (37 mg, 0.26 mmol), K3PO4 (74 mg, 0.35 mmol) and SPhos Pd G3 (6 mg. 0.007670 mmol). Dioxane (7 mL) and water (200 pL) were added. The suspension was bubbled with Ni- The vial was sealed and heated at 100 °C under microwave for 2 h, cooled to room température, and evaporated. The residue was suspended in water, extracted with DCM (3 x). The organic phase was dried over Na₂SO₄, fîltered and evaporated. Silica gel chromatography (4 g silica gel, EtOAc/heptane 0-30%) afforded the product. tert-butyl 4-[l-(2,2dimethylpropanoyI)-5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-pyrrolo[3,2-f]mdazol-7yl]benzoate (58.7 mg, 98 %). *H NMR (300 MHz, Chlorofonn-rf) δ 8.25 (d, J = 8.4 Hz, 2H), 8.10 (d, .7= 0.8 Hz, IH), 8.01 (t, J = 0.9 Hz, IH), 7.58 (d, J = 1.0 Hz, IH), 7.54 - 7.42 (m, 4H), 7.23 (t, J = 8.7 Hz, 2H), 3.90 - 3.79 (m, 2H), 3.20 (td, J = 11.8, 1.9 Hz, 2H), 2.97 (tt, J = 12.3, 3.5 Hz, IH), 1.93 - 1.73 (m, 2H), 1.70 (s, 9H), 1.65 (m, 2H), 1.55 (s, 9H). LCMS m/z 595.42 [M+H]⁴.

Step 7. Synthesis of 4-[5-(4-Jhiorophenyl)-6-tetrahydropyran-4-yl-lH-pvrrolo[3,2-f]indazol-7yl] benzoic acid (331)

A solution of tert-butyl 4-[l-(2,2-dimethyIpropanoyl)-5-(4-fluorophenyl)-6tetrahydropyran-4-yl-pyrrolo[3,2-f|indazol-7-yl]benzoate (58.7 mg, 0.099 mmol) in THF (2 mL) and H₂O (0.5 mL) was treated with LÎOH (200 pL of 5 Μ, 1.0 mmol) for 18 h. The mixture was concentrated. The residue was dissolved in MeOH (1 mL), acidified with 6 N HCI, diluted with DMSO (1 mL), fîltered through cotton plug. The filtrate was purified by reverse H P LC (Waters, acetonitrile/water/O.l % TFA 0-90%). The pure fractions were collected and lyophilized to afford the product. 4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[3,2-f]indazol-7yl]benzoic acid (Trifluoroacetate sait) (27.9 mg, 40 %). ^!H NMR (300 MHz, OMSOF) δ 12.53 (s, 1H), 8.31 - 8.14 (m, 2H), 8.03 (d, J = 1.0 Hz, 1H), 7.77 - 7.62 (m, 2H), 7.62 - 7.47 (m, 3H), 7.46 - 7.30 (m, 2H), 6.79 (s, IH), 3.83 - 3.49 (m, 2H), 3.08 (td, J = 11.2, 4.3 Hz, 2H), 2.93 (p, J = 8.4, 7.6 Hz, 1 H), 1.65 (dd, J = 8.0, 3.3 Hz, 4H). LCMS m/z 456.24 [M+H]⁴.

Compound 332

4-[5-(4-chlorophenyl)-6-tetrahydropyran-4-yl-lH-pyrrolo[3,2-f]indazol-7-yl]benzoic acid (332) 529

Compound 332 was prepared from C232 according to the method described for the préparation of compound 331. ‘H NMR (300 MHz, DMSOA) δ 12.53 (s, IH), 8.23 (d, J = 8.5 Hz, 2H), 8.04 (d, J = 1.0 Hz, IH), 7.70 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 7.56 - 7.49 5 (m, 3H), 6.79 (t, J = 1.1 Hz, IH), 3.88 - 3.60 (m, 2H), 3.09 (dq, J = 11.2, 6.2 Hz, 2H), 2.94 (q, J = 7.4, 6.9 Hz, IH), 1.65 (dd, J = 8.2, 3.2 Hz, 4H). LCMS m/z 472.13 [M+H]⁺.

Compound 333

4-[5-(2-methyl-4-pyridyl)-6-tetrahydropyran-4-yl- lH-pyrrolo[3,2-f] indazol- 7-yl] benzoic acid (333)

Compound 333 was prepared from C232 according to the method described for the préparation of compound 331. NMR (300 MHz, DMSOA) S 13.39 (s, IH), 12.63 (s, IH), 8.77 (d, J = 5.9 Hz, IH), 8.31-8.17 (m, 2H), 8.12 (d, J = 1.0 Hz, IH), 7.91 (d, J = 5.3 Hz, 2H), 7.82 (d, J = 5.7 Hz, IH), 7.72 (d, J = 8.5 Hz, 2H), 6.74 (t, J = 1.1 Hz, IH), 3.75 (d, J = 11.0 Hz, 15 2H), 3.26 - 3.04 (m, 3H), 2.77 (s, 3H), 1.70 (q, J = 12.1, 11.5 Hz, 4H). LCMS m/z 453.22

[M+Hf.

Compound 334

4-(5-(2-methylpyridin-4-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrrolo[3,2-j] indazol- 7(l H)yl)benzamide (334)

530

Compound 334 was prepared from compound 333 according to the method described for the préparation of compound 128. ¹H NMR (400 MHz, MethanolA) δ 8.63 (d, J = 5.8 Hz, 1 H), 8.24 - 8.15 (m, 2H), 8.12 - 8.04 (m, IH), 7.87 (m, IH), 7.82 (m, IH), 7.75 (d, J = 5.8 Hz, IH), 7.67 5 7.60 (m, 2H), 6.84 (t, J = 1.1 Hz, IH), 3.83 (dd, J = 11.6, 4.0 Hz, 2H), 3.25 (m, 2H), 3.18 (m,

IH), 2.78 (s, 3H), 1.84 (qd, J = 12.2, 11.5, 4.1 Hz, 2H), 1.76 (d, J = 13.0 Hz, 2H). LCMS m/z 452.35 [M+Hf.

Compound 335

4-(5- (2-methylpyridin-4-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrrolo[3,2-f] indazol- 7(lH)-yl)-N0 (5-oxopyrroHdin-3-yl)benzamide (335)

Compound 335 was prepared from compound 333 and 4-aminopyrrolidin-2-one by HATU coupling using the method described for the préparation of compound 128. ^JH NMR (400 MHz, MethanolA) δ 8.56 (d, J = 5.3 Hz, 1 H), 8.18 - 8.13 (m, 2H), 8.05 (d, J = 1.1 Hz, IH), 7.72 (d, J = 15 1.2 Hz, IH), 7.67 - 7.59 (m, 2H), 7.56 (br s, IH), 7.49 (dd, J = 5.5, 1.6 Hz, IH), 6.83 (t, J = 1.1

Hz, IH), 4.82 (m, !H), 3.86 (dd, J = 10.6, 7.3 Hz, IH), 3.80 (dd, J = 11.5, 3.9 Hz, 2H), 3.43 (dd, J= 10.5, 4.4 Hz, IH), 3.27-3.17 (m,2H), 3.17-3.04 (m, LH), 2.88 - 2.81 (m, 1 H), 2.68 (s, 3H), 2.49 (dd, J = 17.3, 5.3 Hz, IH), 1.81 (qd, J = 12.3, 1 1.9, 4.2 Hz, 2H), 1.72 (d, J = 12.9 Hz, 2H). LCMS m/z 535.38 [M+H]U

531

Compounds 336 and 337

4-[5-(4-fluorophenyl)-l-methyl-6-tetrahydropyran-4-yl-pyn'olo[2,3-f]indazol-7-yl]benzoic acid (336) and 4-[5-(4-fluorophenyl)-2-methyl-6-tetrahydropyran-4-yl-pyri'olo[2,3-f]indazol-7yl] benzoic acid (337)

To a solution of 33 (50 mg, O.ll mmol) and CS2CO3 (10S mg, 0.33 mmol) in tetrahydrofuran (l mL) was added methyl iodide (17 pL, 0.27 mmol). The reaction mixture was flushed with nitrogen and stirred at 65 °C for 15 h. Méthanol (l mL) and LiOH (500 pL of 2 M, l .0 mmol) were added and further stîrring was continued for 4 h at 65 °C and the mixture was concentrated to dryness, diluted with a mixture of DMSO/water, and injected on a Cl8 50 g cartrîdge. Purification by reversed-phase chromatography (Column: Cl8. Gradient: 10-100 % MeCN in water with O.l % formic acid) afforded 336 (13.5 mg, 49%). ’H NMR (300 MHz, DMSOA) δ 13.25-12.68 (bs, IH), 8.16 - 8.07 (m, 2H), 7.97 (d, J = 0.9 Hz, IH), 7.71 - 7.57 (m, 4H), 7.57 - 7.44 (m, 2H), 7.38 - 7.29 (m, IH), 7.07 (d, J = 1.1 Hz, IH), 3.97 (s, 3H), 3.78 - 3.65 (m, 2H), 3.17 - 2.94 (m, 3H), 1.74 - 1.56 (m, 4H). LCMS m/z 470.3 [M+H] ⁺ and 337 (12.5 mg, 36%). ‘H NMR (300 MHz, DMSO-J₆) δ 13.35-12.5 (bs, IH), 8.26 (s, IH), 8.18 - 8.05 (m, 2H), 7.70-7.56 (m, 4H), 7.56- 7.44 (m, 2H), 7.39 (s, 1H), 6.96 (d, J = 1.2 Hz, 1 H), 4.17 (s, 3H), 3.73 (d, J = 11.0 Hz, 2H),3.18-2.91 (m, 3H), 1.76- 1.54 (m, 4H). LCMS m/z 470.25 [M+H]⁺.

532

Compound 338

4-[5-(3,4-difluorophenyl)-6-(2-methoxy-1,1 -dimethyl-ethyl)-l H-pyrrolo[2,3-fj indazol-7-yl]-3,5dimethoxy-benzoic acid (338)

Step 1: Synthesis of 6-bromo-N-(3,4-difluorophenyl)-l-tetrahydropyran-2-yl-indazol-5-amine (C236)

To a solution of CI84 (20.4 g, 68.88 mmol) and 3,4-difluorophenyl)boronic acid (35.15 g, 222.6 mmol) in dichloromethane (300 mL) was added TEA (32 mL, 229.6 mmol), then 57 g of 3Â sieves were added followed by Cu(OAc)₂ (25.32 g, 204.9 mmol) . The blue-green reaction was stirred at room température for 15 h. The reaction was fdtered, and the filtrate was diluted with dichloromethane (200 mL) and washed with sat. aq. NH₄C1 (500 mL) to which a NH4OH solution (120 mL) had been added. The organic layer was washed with water, separated, dried (MgSO₄), filtered, and evaporated in vacuo to afford a dark brown oil. The oil was dissolved in dichloromethane and filtered over a plug of silica gel. The plug was eluted with 10% EtOAc/dichloromethane until ail of the product had eluted. The filtrate was evaporated in vacuo to afford C236 (15.5 g, 55%). 'H NMR (300 MHz, Chloroformé δ 7.98 - 7.73 (m, 2H), 7.48 (s, IH), 7.05 (dt, J = 10.1, 8.9 Hz, IH), 6.83 (ddd, J = 12.1, 6.8, 2.8 Hz, IH), 6.69 (dtd, J = 8.6, 3.3, 1.6 Hz, IH), 5.79 (s, IH), 5.64 (dd, J = 9.2, 2.5 Hz, IH), 4.03 (ddt, J = 11.7, 3.5, 2.1 Hz, IH), 3.87-3.61 (m, IH), 2.67 - 2.37 (m, IH), 2.11 (dddd, J = 19.4, 13.2, 6.0, 3.4 Hz, 2H), 1.86- 1.57 (m, 3H). ¹⁹F NMR (282 MHz, Chloroformé δ -136.07 (d, J = 22.0 Hz), -147.19 (d, J = 22.0 Hz) ppm. LCMS m/z 408.23 [M+H]⁺;

Step 2: Synthesis of 6-bromo-N-(3,4-difluorophenyl)-lH-indazol-5-amine (C237)

533

To a solution of C236 (1.21 g, 2.96 mmol) in MeOH (20 mL) was added TsOH (Water (1)) (820 mg, 4.31 mmol). The reaction mixture was refluxed for 2 h and was poured into approx. 100 mL of sat. aq. NaHCO₃ (caution: gas évolution was observed). An off-white solid precipitated that was filtered and washed with water. The filter cake was dissolved in EtOAc (50 mL), dried with MgSO₄, and filtered over a plug of silica gel. The plug was eluted with EtOAc and the filtrate was evaporated in vacuo to afford an off-white solid. The solid was triturated with dichloromethane and the solvent evaporated. This was repeated once more and the resulting solid was dried in vacuo to afford C237 (900 mg, 94%). ^]H NMR (300 MHz, DMSOA) δ 13.14 (s, IH), 8.10 - 7.86 (m, 2H), 7,76 (d, J = 30.4 Hz, 2H), 7.1 8 (dt, J = 10.7, 9.1 Hz, IH), 6.64 (ddd, J = 13.3, 7.0, 2.7 Hz, IH), 6.50 (dq, J = 9.6, 2.6, 2.1 Hz, IH). ¹⁹F NMR (282 MHz, DMSOA) δ -138.14 (d, J = 23.2 Hz), -152.57 (d, J = 23.1 Hz) ppm. LCMS m/z 324.06 [M+H]⁺;

Step 3: Synthesis of methyl 4-(5-(3,4-difluorophenyl)-6-(2-methoxy-l,1-diméthyl-ethyl)-!Hpyrrolo[2,3-fj indazol- 7-yl]-3,5-dimethoxy-benzoate (C239)

A solution of C237 (50 mg, 0.15 mmol), C238 (60 mg, 0.18 mmol) and 7V-cyclohexyl-/Vmethyl-cyclohexanamine (100 pL, 0.47 mmol) in 1,4-dioxane (1 mL) was degassed with nitrogen for 10 min. Then, Pd(r-Bu₃P)2 (6 mg, 0.012 mmol) was added and the reaction was degassed for an additional 5 min, then heated at 105 °C and stirred for 15 h. The reaction was cooled to room température, diluted with water, and extracted with EtOAc. The organic layer was passed through a phase separator and concentrated. The crude materiai was purified by silica gel chromatography (24 g column, 0-30% EtOAc/Heptane) to afford C239 (38 mg, 45%) LCMS m/z 550.32 [M+H]+;

Step 4: Synthesis of 4-(5-(3,4-difluorophenyl)-6-(2-methoxy-l,l-dimethyl-ethyl)-lH-pyrrolo(2,3f]indazol-7-yl]-3,5-dimethoxy-benzoic acid (338)

To a solution of C239 (38 mg, 0.07 mmol) in THF (1 mL), MeOH (0.5 mL) and water (0.5 mL) was added LiOH (16.56 mg, 0.7 mmol). The reaction was stirred at room température for 45 min. The reaction was then acidified with \M HCl, extracted with EtOAc, and concentrated. The crude materiai was purified by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 xl50 mm, 5 micron). Gradient; MeCN in water with 0.1% trifluoroacetic acid to afford 338 (13.2 mg, 33%). ^lH NMR (4Ü0 MHz, DMSOA) δ 12.38 (s, IH), 7.94 (d, J = L0 Hz, IH), 7.76 - 7.63 (m, 2H), 7.36 (s, 3H), 6.86 (d, J = 1.1 Hz, IH), 6.68 (t, J = 1.1 Hz, IH), 3.74 (s, 6H), 3.07 (d, J = 2.7 Hz, 2H), 3.00 (s, 3H), 1.08 (s, 7H). LCMS m/z 536.21 [M+H]⁺;

534

Compound 339 methyl 5-[5-(4-fluoro-3-methyl-phenyl)-6-tetrahydropyran-3-yl-IH-pyrrolo[2,3-f]indazol-7-yl]6-methoxy-pyridine-2-carboxylate (339)

Step 1: Synthesis of methyl 5-[5-(4-fluoro-3-methyl-phenyl)-6-tetrahydropyran-3-yl-lHpyrrolo[2,3-f]indazol- 7-yl]-6-methoxy-pyridine-2-carhoxylate (C241)

A solution of C240 (300 mg, 1.09 mmol), Cl95 (351 mg, 1.096 mmol), Pd(/-Bu₃P)₂ (60 mg, 0.12mmol) and /V-cyclohexyl-A-methyl-cyclohexanamine (912 mg, 4.7 mmol) were mixed in dioxane (5 mL) and the reaction was degasscd with nitrogen for 1 min. The reaction was heated at 120 °C for 15 h. The reaction was cooled to room température and was diluted with EtOAc and washed with water and brine. The organic layer was dried and concentrated and the residue was purified by silica gel chromatography (40 g silica gel, 10-90% EtOAc în hexanes) to afford C241 (180 mg, 29%). LCMS m/z 515.35 [M--H]⁺;

Step 2: Synthesis of 5-[5-(4-fluoro-3-methyl-phenyl)-6-tetrahydropyran-3-yl-lH-pyrrolo[2,3f] indazol- 7-yl]-6-methoxy-pyridine-2-carboxy lie acid (339)

To a solution of C241 (160 mg, 0.31 mmol) in THF (8 mL), MeOH (4 mL) and water (4 mL) was added LiOH H₂O (158 mg, 3.8 mmol). The reaction was stirred at 60 °C for 15 h. Then, after cooling to room température, IM HCl was added to carefully adjust the pH to 5, and the reaction was extracted with dîchloromethane (10 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by reversed-phase chromatography (10-90% 535 water-acetonitrile, 0.1% formic acid) to afford 339 (130 mg, 79%). ^lH NMR (400 MHz, DMSOcl_b) δ 13.20 (s, IH), 12.68 (s, IH), 8.05 (s, IH), 7.94 - 7.80 (m, 2H), 7.70 (dd, J = 7.4, 1.0 Hz, IH), 7.42 (dd, J = 3.6, 1.0 Hz, IH), 7.26 (s, IH), 7.15 (t, J = 9.1 Hz, IH), 7.01 (s, IH), 4.01 3.78 (m, 3H), 3.54 - 3.29 (m, 2H), 2.97 - 2.75 (m, IH), 2.20 (s, 3H), 1.92 (q, J = 14.4, 13.6 Hz, 5 IH), 1.63 (d, J = 20.6 Hz, 2H). LCMS m/z 501.22 [M+H]⁺;

Compound 340

4-[6-(2-cyano-l,l-dimethyl-ethyl)-5-(4-fluoro-3-methoxy-phenyl)-lH-pyrrolo[2,3-j]indazol-7yl] -2-methoxy-benzoic acid (340)

O.

Aoh a-a LiOH \A

H Γ -----N-AAA I OIM

340 Λ

F

Compound 340 was prepared from intermediate Cl84 using the proper reagents to generate C241 and C242 using the same procedures as for compound 338. *H NMR (400 MHz, MethanolA) δ 8.05 - 7.93 (m, 2H), 7.40 (dd, J = 11.1, 8.5 Hz, IH), 7.33 (d, J = 1.4 Hz, IH), 7.31 - 7.23 (m, IH), 7.18 (td, J = 9.3, 8.6, 2.4 Hz, 2H), 7.04 (dt, J = 15.2, 1.2 Hz, 2H), 3.95 (d, J 15 = 1.1 Hz, 3H), 3.91 (s, 3H), 2.72 - 2.52 (m, 2H), 1.38 (t, J = 6.2 Hz, 6H). LCMS m/z 513.27

[M+H]⁺.

536

Compound 341

4-[6-[l-(cyanomethyl)cyclobutyl]-8-fluoro-5-(3-fluoro-5-methoxy-phenyl)-lH-pyrrolo[2,3f]indazol-7-yl]benzoic acid (341)

C244 C245

XantPhos Pd G3

NaOf-Bu

Pd(tBu₃P)_z

341

Step 1: Synthesis of 6-bromo-7-fluoro-5-iodo-lH-indazole (C245)

To a solution of C244 (114.7 g, 330.6 mmol) în 2-MeTHF (700 mL) was added hydrazine HiO (100 mL, 2.040 mol) and the reaction was refluxed for 4 days. The reaction was poured into water (500 mL) and extracted with MTBE (500 mL). The organic layer was separated, dried over MgSO₄ and evaporated in vacuo. The solid that remained was triturated with heptane and dried in vacuo to afford C235 (60 g, 53%). ^!H NMR (300 MFIz, DMSOA) δ 13.92 (s, IH), 8.26 (s, 1 H), 8.16 (d, J = 3.4 Hz, 1H). ^I9F NMR (282 MHz, DMSOA) δ -113.46. LCMS m/z 340.72 [M+H]+;

Step 2: Synthesis oj 6-bromo-7-fluoro-N-(3-fluoro-5-methoxy-phenyl)-lH-indazol-5-amine (C246)

A solution of C245 (1 g, 2.933 mmol), 3-fluoro-5-methoxy-aniline (493 pL, 4.108 mmol) and NaOt-Bu (705 mg, 7.336 mmol) in dioxane (11.75 mL) was purged with nitrogen for 10 min. Then, XantPhos Pd G3 (279 mg, 0.2942 mmol) was added and the reaction was purged with nitrogen for another 5 min. The reaction was then stirred at 90 °C for 15 h. The reaction was cooled down and EtOAc (120 mL) was added followed by aq. sat. NH₄C1 and 6M HCl to adjust the pH to - 2. The two layers were separated, and the organic layer was washed with \M HCl, concentrated to dryness. The residue was purified by silica gel chromatography (Gradient: ΟΙ 00% EtOAc in heptane) to afford C247 (357 mg, 34%). NMR (400 MHz, DMSOA) δ

537

13.76 (s, IH), 8.17 (s, IH), 7.99 (s, IH), 7.59 (s, IH), 6.18 -6.12 (m, 2H), 6.08 (dt, J = 11.4, 2.1 Hz, IH), 3.67 (s, 3H). LCMS m/z 354.01 [M+H]⁺;

Steps 3 and 4: Synthesis of 4-[6-[ l-(cyanomethyl)cyclobutyl] -8-fluoro-5-(3-fluoro-5-methoxyphenyl)-lH-pyrrolo[2,3-f] indazol-7-yl] benzoic acid (341)

A solution of C246 (59 mg, 0.16 mmol) and C196 (85 mg, 0.34 mmol) in dioxane (865 pL) was bubbled with nitrogen for 2 min. Then, ÀAyclohexyl-A-methyl-cyclohexanamine (89 pL, 0.41 mmol) was added and nitrogen was bubbled through for 5 min. Then, Pd(/Bu3P)₂ (9 mg, 0.018 mmol) was added and nitrogen was bubbled through for another 5 min. The reaction was stirred at 80°C for 15 h. Then, additional Pd(/Bu₃P)₂ (9 mg, 0.01761 mmol) was added and the reaction was stirred at 100 °C for 2 h and cooled down to 50 °C. Méthanol (1.2 mL), THF (1.2 mL) and LÎOH (650 pL of 2.5M, L63 mmol) were successively added and the reaction was stirred at 50 °C for 1 h. The reaction mixture was concentrated to dryness and diluted with a DMSO/water (2:1, 2mL) and purified by reversed-phase chromatography (Column: Cl 8. Gradient: 0-100 % acetonitrile in water with 0.1 % formic acid) to afford 341 (22.9 mg, 26%).

*H NMR (400 MHz, DMSO-d6) δ 13.10 (s, IH), 12.99 (s, IH), 8.09 (d, J = 3.3 Hz, IH), 8.03 7.95 (m, 2H), 7.74 (dd, J = 8.3, 1.5 Hz, 2H), 7.18 (dt, J = 9.1, 2.1 Hz, 1 H), 7.16 - 7.12 (m, 1 H), 7.12 - 7.09 (m, IH), 6.94 (s, IH), 3.85 (s, 3H), 3.23 (s, 2H), 2.35 - 2.23 (m, 2H), 1.94 (p, J = 9.4 Hz, IH), 1.58 - 1.42 (m, 3H). LCMS m/z 513.22 [M+H]⁺;

538

Compound 342

4-[6-[l-(cyanomethyl)cyclobutyl]-3-fluoro-5-(4-fluorophenyl)-lH-pyrrolo[2,3-J] indazol- 7yl] benzoic acid (342)

Step 1: Synthesis of 6-bromo~3-fluoro-5-mtro-lH~indazole (C250)

To a solution of C249 (2.41 g, 10 mmol) in acetonitrile (20 mL) and AcOH (20 mL) was added Selectfluor® (3.53 g, 11 mmol). The mixture was stirred at 100 °C for 16h. After cooling down, the salts were fîltered out, the resulting filtrate was concentrated to give C250 (1,14 g, 44%). LCMS m/z (M+lf: 260.0.

Step 2: Synthesis of 6-bromo-3-fluoro-5-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (C251)

To a solution of C250 (2 g, 7.7 mmol) in dichloromethane (20 mL), was added TsOH (1.46 g, 8.47 mmol). The mixture was stirred at room température for 24h and then poured into water (50 mL) and extracted by EA (50 mL x 3). The organic layer was concentrated under vacuum and purified by silica gel chromatography (gradient: EtOAc 50% in heptane) to give C251 (1.3 g, 50%). LCMS m/z (M+H)⁺: 344.0

Step 3: Synthesis of 6-bromo-3-fluoro-I-(tetrahydro-2H-pyran-2-yl)-lH-indazol-5-amine (C252)

To a mixture of C251 (1.3 g, 3.8 mmol) in methanol (30 mL), was added zinc powder (1.23 g, 19 mmol, 5 eq) and NH4OAc (0.45 g, 5.7 mmol, 1.5 eq). The mixture was stirred at rt

539 for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient; EtOAc 50% în heptane) to give C252 (350 mg, 29%). ^lH NMR (400 MHz, DMSO-rf6) Æ 7.95 (s, IH), 6.92 (s, IH), 5.57 (d, J = 7.2 Hz, IH), 5.20 (s, 2 H), 3.85-3.81 (m, IH), 3.72-3.68 (m, IH), 2.20-2.15 (m, IH), 1.98-1.94 (m, IH), 1.89-1.85 (m, IH), 1.68-1.65 (m, IH), 1.55-1.49 (m, 2H). LCMS m/z (M+H)⁺: 314.1.

Step 4: Synthesis of 6-bromo-3fhioro-N-(4-fluorophenyl)-I-tetrahydropyran-2-yl-indazol-5amine (C252)

To a suspension of 1g of 3Â molecular sieves, C251 (1 g, 3.18 mmol) and (4fluorophenyl)boronic acid (1.44 g, 10.3 mmol) in dichloromethane (15 mL) was added TEA (1.5 mL, 10.8 mmol) and Cu(OAc)₂ (1.75 g, 9.64 mmol). The reaction was stirred at 4h and Celite® was added and the mixture was concentrated to dryness. The residue was dry loaded on an 80gram Si gold cartridge. (Gradient: 0- 100 % EtOAc in heptane) to afford C252 (860 mg, 62%). ’H NMR (400 MHz, DMSOé) δ 8.21 (d, J = 2.0 Hz, IH), 7.55 (s, IH), 7.39 (s, IH), 7.09 - 7.00 (m, 2H), 6.96 - 6.88 (m, 2H), 5.80 (dt, J = 9.7, 2.6 Hz, IH), 3.92 - 3.83 (m, IH), 3.79 - 3.69 (m, IH), 2.26 - 2.16 (m, IH), 2.04 - 1.96 (m, IH), 1.96 - 1.88 (m, IH), 1.76 - 1.64 (m, IH), 1.59 1.50 (m, 2H). LCMS m/z 408.15 [M+H]+;

Steps 5-7: Synthesis of 4-[6-[l-(cyanomethyl)cyclobutyl]-3-fluoro-5-(4-fluorophenyI)-lHpyrrolo[2,3-f]indazol-7-yl]benzoic acid (342)

To a solution of C196 (63 mg, 0.2483 mmol) and C252 (53 mg, 0.1215 mmol) in dioxane (745 pL) was added A-cyclohexyl-A-methyl-cyclohexanamine (67 pL, 0.3128 mmol) and the mixture was bubbled nitrogen for 5 min. Then, Pd(tBu₂P)₂ (6.5 mg, 0.013 mmol) was added and nitrogen through the mixture for an additional 5 min. The reaction was stirred at 80 °C for I5h. The reaction mixture was concentrated to dryness and afford crude C253 which was taken directly to the next step.

A solution of the crude from the previous step in MeOH (1 mL) and HCl (203 pL of 6M, 1.218 mmol) was stirred at 50 °C for 1 h. LCMS showed the desired product and THF (1 mL) was added to the solution. Then, LiOH (975 pL of 2.5M, 2.44 mmol) was added and the mixture was stirred for 15 min at 50 °C and concentrated to dryness. The residue was purified by silica gel chromatography on a Si gold 12-gram column. (Gradient: 0- 10 % mcthanol in dichloromethane) to yield 342 (12.6 mg, 20%). ‘H NMR (400 MHz, DMSO-J₆) δ 13.05 (s, IH), 12.02 (s, IH), 8.13 - 8.01 (m, 2H), 7.79 - 7.72 (m, 2H), 7.72 - 7.63 (m, 2H), 7.55 - 7.41 (m, 2H), 7.24 - 7.12 (m, IH), 6.85 (s, IH), 3.19 (s, 2H), 2.36 - 2.22 (m, 2FI), 1.99 - 1.88 (m, IH), 1.60 1.45 (m, 3H). LCMS m/z 483.22 [M+H]⁺

540

EXAMPLE 2. Assays for Detecting and Measuring AAT Modulator Properties of Compounds

A. AAT Function Assay (MSD Assay NL20-SI Cell Line)

Alpha-1 antitrypsin (AAT) is a SERPIN (serine protease inhibitor) that inactivâtes enzymes 5 by binding to them covalently. This assay measured the amount of functionally active AAT in a sample in the presence of the disclosed compounds 1-342 by determinîng the ability of AAT to form an irréversible complex with human neutrophil Elastase (hNE). In practice, the sample (cell supernatant, blood sample, or other) was incubated with excess hNE to aïlow AAT-Elastase complex to be formed with ail functional AAT in the sample. This complex was then captured 10 to a microplate coated with an anti-AAT antibody. The complex captured to the plate was detected with a labeled anti-Elastase antibody and quantitated using a set of AAT standards spannîng the concentration range present in the sample. Meso Scale Discovery (MSD) plate reader, Sulfo-tag labeling, and microplates were used to provide high sensitivity and wide dynamic range.

MATERIALS:

Reagents/Plates	Concentration
Goat anti-human Alpha-1 -Antitrypsin Polyclonal Antibody Use at 5 pg/mL in phosphate buffered saline (PBS)	1 mL @ 1 mg/mL
Human Neutrophil Elastase Stock at 3.4 pM (0.1 mg + 1 mL PBS) Working at 1 pg/mL (34um) m MSD Assay buffer (1% bovine sérum albumin (BSA))	100 pg lyophilized
Mouse anti-human Neutrophil Elastase Monoclonal Antibody Sulfo-tagged @ 12:1 using MSD Gold Sulfo-tag Nhydroxysuccinimide (NHS) ester; use at 0.45 pg/mL in MSD Assay buffer (1% BSA)	900 pgzmL
M-AAT (Alpha-1-Antitrypsin)	5 mg lyophilized
MSD Blocker A (BSA) 5% solution in PBS forblocking 1 % solution in PBS for assay buffer	250 mL
MSD Read Buffer T (4X) with Surfactant MSD 384 high bind plates Polypropylene for dilution 384 well plate Tissue culture treated black well 384 well plate	1 L or 250 mL

INSTRUMENTAS!:

Meso Sector S600 Bravo

Washer dispenser

Multidrop Combi

541

ASSAY PROTOCOL

Day 1 Cell Culture

1. Harvest NL20 human bronchial épithélial cells expressing human Z-AAT in OptiMEM™ containing Pen/Strep (P/S)

2. Seed at 16,000 cells/well în 30 pL (384 well plate)

3. Centrifuge plates briefly up to speed (1200 rpm) and place into 37°C incubator overnight Day 2; Compound Addition and Coating Plates with Capture Antibody

Compound Addition:

1. Dispense 40 pL of OptiMEM™ (P/S) with doxycycline (1:1000 stock = 0.1 pM final) to each well of the compound plate using a multîdrop Combi in hood

2. Remove cell plate from incubator, flip/blot and take immediately to Bravo to transfer compounds

3. Return plates to incubator overnight

Coat MSD Plates

1. Dilute capture antibody (Polyclonal Goat anti-AAT) to 5 pg/mL (1:200) in PBS (no BSA).

2. Dispense 25 pL of diluted capture antibody into ail wells of MSD 384-well High Bind plate using the Multidrop equipped with a standard cassette.

3. Incubate overnight at 4°C

Préparé Blocker A (BSA) Solutions

1. Préparé solution of 5% MSD Blocker A (BSA) following the manufacturer’s instructions.

2. Further dilute the 5% MSD Blocker A in PBS to 1 % (Blocker A) as needed.

Day 3: Run MSD Assay

Block Plates

1. Wash plate lx with 50 pL Wash buffer (PBS + 0.5% Tween 20), and adds 35 pL 5% Block A buffer to block non-specific binding on washer dispenser

2. Rotate plates on shaker for 1 hour at 600 rpm

Préparé M-AAT Standards

1. Dilute M-AAT stock to 1.6 pg/mL in 1% BSA Blocker A (Stock în -70°C); then préparé 12 x 1:2 serial dilutions in 1% Blocker A

2. The top starting final concentration on MSD plate is 320 ng/mL. These dilutions correspond to a final concentration of 320, 160, 80, 40, 20, 10, 5, 2.5, 1.25, 0.625, 0.312, 0.156 ng/mL.

542

Dilution plate

l. Add 80 pL of l % Assay buffer to ail wells except columns l/24 (standards) with Multidrop Combi

2. Add diluted standards to columns 1 and 24

3. Centrifuge dilution plates 1200 rpm briefly

Cell plate

1. Aspirate columns which will hâve the standards from the cell plates in the hood using 16pin aspirator

Préparé human Neutrophil Elastase (hNE)

1. Préparé 1 pg/mL Human Neutrophil Elastase by diluting in 1% Blocker A.

a. Small 100 pg via! - add 1 mL PBS (100 pg/mL)

i. This can then be diluted 1:100 in 1% Assay Buffer for a final 1 pg /mL concentration

MSD - add hNE (20 pL/well)

1. After the MSD plate has blocked for ai least 1 hour, wash plate Ix with 50 pL Wash buffer (PBS + 0.5% Tween 20) and then add 20 pL hNE to each well

Bravo - Cell Plate - Dilution Plate - MSD Plate

Using the Bravo aspirate 10 pL from the cell plate, transfer to the dilution plate (9-fold dilution)

1. Mix 25 pL 3x, then aspirate 5 pL, transfer to MSD plate (5-fold dilution)

2. Mix 10 pL 3x. Total dilution is 45-fold.

3. Shake plates at 600 rpm for 1.5 hours

Add Functional détection hNE antibody

1. Wash plate 1X with wash buffer

2. Add 25 pL Sulfo-tagged anti-Elastase Monoclonal Mouse anti-Elastase) diluted to 0.45 pg/mL (1:2000) in 1% Blocker A into ail wells of the functional activity MSD plates using the washer/dispenser

Note: The dilution required for suffi ci ent signal must be determined for each new lot of labeled antibody.

3. Incubate at RT shaking at 600 rpm for 1 hour.

Final wash and MSD imager read

1. Wash the plate 1 x, and add 25 pL of Wash Buffer to the plate.

2. Make 2 x Read buffer

3. Remove wash buffer from MSD plate

4. Transfer 35 pL 2x Read Buffer to MSD plate using Bravo and take to MSD to read immediately

543

Data analysis in MSD Discovery Workbench 4.0 software and EC50 values were determined using Genedata. See Table 22 for data.

B. Biochemical Assay (Z-AAT Elastase Activity Assay)

This assay measured the modulation of compounds 1-342 on Z-AAT SERPIN activity using purified Z-AAT protein and purified human neutrophil elastase (hNE). Normally, when active monomeric Z-AAT encounters a protease such as trypsîn or elastase, it forms a 1:1 covalent “suicide” complex in which both the AAT and protease are irreversibly inactivated. However, compounds binding to Z-AAT can lead to a decrease in SERPIN activity. In such cases, when a protease encounters compound-bound Z-AAT, the protease cleaves and inactivâtes Z-AAT without itself being inactivated.

MATERIALS

Reagents

PBS buffer (media prep) + 0.01% BRIJ35 detergent (Calbiochem catalog #20372$) Opti-MEM media (Fisher 11058-021)

Human neutrophil elastase (hNE, Athens Research #16-14-051200)

3.4 μΜ stock (0.1 mg/mL) prepared in 50mM Na Acetate, pH 5.5, 150mM NaCI, stored at -80°C

Elastase sub strate V (ES V, fluorescent peptide substrate MeOSuc-Ala-Ala-Pro-ValAMC, Calbiochem catalog #324740) mM stock in DMSO, stored at -20°C Purified Z-AAT protein from human plasma;

12.9 μΜ (0.67 mg/mL) Z-AAT Vertex Cambridge Sample 4942, from patient #061-SSN, stored at-80C

Plates

Corning 4511 (384 well black low volume)

Instruments

PerkinElmer® EnVision™

ASSAY PROTOCOL

Pre-incubation of Z-AAT with Compounds

1. 7.5 pL of Z-AAT (20 nM) was incubated with compounds 1-342 in a GCA plate for 1 hour at room température

Addition of hNE

1. 7.5 ul of HNE solution (3 nM in PBS+0.01% BRIJ35) added into GCA plate

2. Incubate plate for 30 minutes to allow Z-AAT/HNE suicide complex formation.

Addition of substrate and read plate on PE Envision

544

l. 7.5 pL of substrate (300 pM solution of elastase substrate (ES V) in PBS+0.0l% BRIJ35) dispensée! per well into GCA plate

2. Immediately read on Envision.

C. ICso and ECso DATA FOR COMPOUNDS 1 - 342

The compounds of fonnula (I) are usefui as modulators of A AT activity. Table 22 below illustrâtes the IC₅₀ and EC50 of the compounds 1-342 using procedures described above (assays described above in Example 2A). In Table 22 below, the following meanings apply. For IC50 and EC50: “+++” means < 0.4 pM; “++” means 0.4 μΜ to 1.0 pM; “+” means greater than 1.0 10 pM; and “N/A” means activity not assessed. For IC₅o, “N.D.” means activity not detected up to 30 pm.

Table 22. IC^o and EC50 data for Compounds 1-342

Compound	Z-AAT Elastase Activity (IC50)	NL20 Func. (ECso)
1	+	+++
2	+	+++
3	N.D.	4-4-
4	+	++
5	N.D.
6	N.D.	+
7	+	H—1—h
8	+	++
9	N.D.	++
10	+	H—H-
11	+	+++
12	N.D.	“T
13	4“	+++
14	N.D.	+
15	N.D.	++
16	N.D.	+
17	N.D.	+4-
18	N.D.	+
19	N.D.	+
20	N.D.	+++
21	N.D.	++
22	N.D.	4-
23	N.D.	+
24	N.D.	4~
25	+	+
26	N.D.	+
27	+	4-

545

Compound	Z-AAT Elastase Activity (IC50)	NL20 Func. (ECS0)
28	N.D.	’F
29	N.D.	-h “H H-
30	N.D.	++
31	+	++
32	+	++
33	+	+++
34	H-	+
35	+	4-4-4-
36	+	+
37	+	I | |
38		4-4-
39	+	-H-
40	N.D.	+4-
41	N.D.	++
42	N.D.	+
43	N.D.	+
44	N.D.	+
45	+	I | |
46	N.D.	4-4-4-
47	+	I | |
48	+	++
49	+	I | |
50	-H	I | |
51	+	+++
52	+	++
53	Η-	+++
54	+	+++
55		H—H+
56	+++	+++
57	4-	+++
58	+	+++
59		++
60	+	-H-
61	N.D.	4-4-
62	N.D.	+
63	N.D.	+
64	N.D.	+
65	N.D.	++
66	+	+
67	+	+++
68	+	+++
69		+++
70	T	4-4—H

546

Compound	Z-AAT Elastase Activity (IC30)	NL20 Func. (EC50)
71	H-	+++
72	+	+++
73	N.D.	+++
74	+	+++
75	4-	+++
76	N.D.	+++
77	4-	Ή 4—H
78	N.D.	++
79	+	+~l·
80	4-	++
81	4-	_!__L
82	H-	n—
83	d-	“i—r
84	4-	d--i-
85	+	d-+
86	N.D.	-r
87	-H	d-
88	N/A	d-
89	+	+
90	N.D.	+
91	N.D.	+
92	d	+
93	N.D.	+
94	N.D.	+
95	N.D.	4-
96	N.D.	4-
97	+	4—1—l·
98	+	++
99	N.D.	+
100	4-	+
101	N.D.	4-4-4-
102	++	+++
103	N.D.	+
104	4Ά	+++
105	+	4-++
106	4-	++
107	N.D.	+
108	H—H	+++
109	4-	+++
110	+	+++
111	d-	+++
112	4-	+++
113	+	+++ |

547

Compound	Z-AAT Elastase Activity (IC50)	NL20 Func. (EC50)
114	+	4-4-4-
115	N.D.	+4-
116	+	t [ |
117	+	-H-+
118	+	+
119	+	++
120	+	+
121	N.D.	-H-
122	N.D.	+
123	+	4—1—1-
124	+	+++
125	++	+++
126		+
127	N.D.	+++
128	+	+++
129	+	+++
130	N.D.	++
131	N.D.	+
132	N.D.	++
133	N.D.	+
134	N.D.
135	+	+
136	+	1 |
137	N.D.	4-
138	N.D.	++
139	N.D.	++
140	N.D.	+
141	N.D.	+
142	N/A	+
143	N.D.	+
144	N.D.	+++
145	N.D.	4-4-
146	N.D.	+
147	N.D.	+
148	N.D.	+
149	X	+
150	N.D.	+++
151	N.D.	+
152	N.D.	+
153	N.D.	4-h
154	N.D.	+
155	N/A	4-
156	N.D.	+

548

Compound	Z-AAT Elastase Activity (IC50)	NL20 Func. (EC$0)
157	N.D.	+
158	N.D.	+
159	+	+
160	+	+
161	N.D.	+
162	+	+
163	N.D.	+
164	+	++
165	N/A.
166	+	-H
167	-f-	+
168	+	+
169	N.D.	-f-
170	+	+
171	N.D.	+
172	+
173	_L	+
174	N.D.	-pj—H
175	N.D.	-f-
176	-H	+
177	N/A	+
178	+	+
179	N.D.	+
180	N.D.
181	+++	N/A
182	+++	+++
183	++	+++
184	+	+++
185	+	+++
186	++	+++
187	++	++
188	+
189	-H-	+++
190	++	++
191	+	+++
192	-i-	++
193	+	+
194	-H	4-
195	N/A	+
_ 196	+	++
197	++	+++
198	+	+
199	+	+

549

Compound	Z-AAT Elastase Activity (IC50)	NL20 Func. (EC50)
200	+	_L
201	4-	4-
202	Ί-	+”0
203	+	+4-
204	N.D.	++
205	N.D.	++
206	N.D.	+
207	4-	4-
208	N.D.	4-
209	N.D.	+
210	N.D.	4-
211	N.D.	4-
212	+	+
213	N.D.	+
214	-1-	+
215	N.D.
216	N.D.	+
217	+	4-
218	“T	4-4-
219	N.D.	-h
220	+	+4-
221	N.D.	+
222	4-	4-
223	4-	+
224	N.D.	+
225	N.D.	++
226	N.D.	4-
227	N.D.	+
228	+	4-
229	N.D.	+
230	+	4-
231	4-	+4-
232	+	4-4-
233		1-
234		4-
235	4-	4-
236	N.D.	4-
237	-1-	4-
238	4-	4-4-
239	N.D.	h
240	N.D.	4-
241	N.D.	4-
242	+	++

550

Compound	Z-AAT Elastase Activity (IC5Ü)	NL20 Fune. (EC50)
243	+	+
244	f	+
245	+	++
246	+	++
247	4-	++
248	N.D.	+
249	N.D.	+
250	N.D.	+
251	N.D.	+
252	4-	+++
253	+++	+++
254	+	++
255	+	+
256	+	+++
257	N.D.	+
258	N.D.	++
259	N.D.	+
260	N.D.	+
261	N.D.	+
262	+	+
263	N.D.	+
264	N.D.	+
265	+	4-4-4-
266	N.D.	4-
267	H-	H—HH-
268	++	+++
269	+	+++
270	+	+++
271	4-4-	+4-4-
272	H-	+
273	N.D.	++
274	N.D.	4-
275	+	4-
276	N.D.	-h
277	+	+
278	+	++
279	N.D.	+
280	N.D.	+
281	N.D.	+
282	N.D.	+
283	N.D.	+
284	+	+++
285	N.D.	4-

551

Compound	Z-AAT Elastase Activity (IC50)	NL20 Func. (EC5Ü)
286	4-	+
287	N.D.	4-
288	N.D.	4-
289	N.D.	++
290	+	+
291	+	4-4-4-
292	N.D.	4-
293	N.D.	4-
294	N.D.	4-
295	N.D.	+
296	+	4-
297	N.D.
298	+	+
299	4-	4-
300	N.D.	4-
301	“T	4-4-
302	N.D.	T
303	+	+
304	4-	4-4-4-
305	N.D.	4-
306	4-	4-
307	N.D.	4-
308	N.D.	4-
309	N.D.	+
310	N.D.	4-
311	N.D.	+
312	N.D.	+
313	4-	4-
314	+	+
315	N.D.	4-
316	N.D.	+
317	+	H—H
318	N.D.	+
319	4-	4-
320	4-4-	4-4-4-
321	4-	4-4-4-
322	N.D.	4-
323	N.D.	4-
324	N.D.	4-
325	N.D.	4-
326	N/A	4-
327	4-	-H
328	4-	Ή

552

Compound	Z-AAT Elastase Activity (ICSfl)	NL20 Func. (ECS())
329	N.D.	+
330	+	+
331	+	+++
332	+	++
333	N.D.	+
334	N.D.
335	N.D.
336	N.D.	+
337	N.D.	+
338	+	N/A
339	N.D.	+
340	N/A	N/A
341	N/A	N/A
342	-f-+	N/A

Example 3: Solid Forms of Compound 33

Bruker-Biospin 400 MHz wide-bore spectrometer equipped with B ruker-Biospin 4mm HFX probe was used. Samples were packed into 4mm ZrO₂ rotors and spun under Magic Angle Spinning (MAS) condition with spinning speed typically set to 12.5 kHz. The proton relaxation time was measured using ’H MAS Tj saturation recovery relaxation experiment in order to set up proper recycle delay of the ^l3C cross-polarization (CP) MAS experiment. The fluorine relaxation time was measured using ⁱ⁹F MAS T| saturation recovery relaxation experiment in order to set up proper recycle delay of the ^l9F MAS experiment. The CP contact time of carbon CPMAS experiment was set to 2 ms. A CP proton puise with linear ramp (from 50% to 100%) was employed. The carbon Hartmann-Hahn match was optimized on external reference sample (glycine). Both carbon and fluorine spectra were recorded with proton decoupling using TPPM15 decoupling sequence with the field strength of approximately 100 kHz.

1. Compound 33 Form A

A. Synthetic Procedure

Methyl 4-(5-(4-fluorophenyl)-l-pivaloyl-6-(tetrahydro-2H-pyTan-4-yl)-l,5dihydropyrrolo[2,3-f]indazol-7-yl)benzoate (25.1 g, 45.337 mmol) was dissolved in THF (326.3 mL, 13 vol). Sodium hydroxide [2N] (5.44 g, 68.0 mL, 136.01 mmol, 3 equiv) was added and the mixture was heated to 55 -60 °C. Upon reaction completion, the reaction mixture was cooled to 20 °C and water (75.3 mL, 3 vol) and acetic acid (10.89 g, 10.38 mL, 181.35 mmol, 4 equiv.) was added thereto. 2-MeTHF (251 mL, 10 vols) was added aqueous work up was performed. The organic layer was washed with water (75.3 mL, 3 vol) followed by a 6.5 wt% sodium

553 chloride solution by dissolving NaCl (8.2g, 0.14mmol, 3.1equiv) in water (0.120 L, 4.7 vol). The organic layer and solvent swap were distîlled into éthanol. A mixture of EtOH (0.150 L, 6 vol) and water (25.1 mL, l vol) was added and distillation was continued, and this step was repeat once. EtOH (0.150 L, 6 vol) and water (25.1 mL, l vol) were added to the reactor and the mixture was stirred at 40 °C. The mixture was cooled to 20 - 25 °C and the product was isolated b y filtration. Compound 33 was dried under vacuum at 66 °C with nitrogen bleed. Compound 33 was isolated in 90% yield with > 99.8% area.

B. X-Ray Powder Diffraction

X-ray powder diffraction (XRPD) spectra were recorded at room température in reflection mode using a PANalytical Empyrean system equipped with a sealed tube source and a PIXcel l D Medipix-2 detector (Malvem PANalytical Inc, Westborough, Massachusetts). The X-Ray generator operated at a voltage of 45 kV and a current of 40 mA with copper radiation (L54060 Â). The powder sample was placed in a back filled sample holder and loaded into the instrument. The sample was scanned over the range of about 3° to about 40° 2Θ with a step size of 0.0131303° and 49.725s per step. The XRPD diffractogram is shown in FIG. IA and XRPD data are summarized in Table 23.

Table 23: XRPD Peaks for Compound 33 Form A

Peak #	Angle (Degrees 2-Theta ±0.2)	Intensity %
I	19.2	100.0
2	16.0	26.8
3	19.5	25.1
4	14.2	24.3
5	16.2	20.9
6	15.5	20.8
7	21.8	20.2
8	11.0	20.0
9	21.3	17.1
10	20.9	14.7
11	17.5	13.4
12	25.5	10.4

C. Solid State NMR (1) ¹³C CPMAS Analysis

Solid State ¹³C NMR data for Compound 33 Form A îs provided in FIG. IB and summarized în Table 24 below.

Table 24: Solid State NMR of Compound 33 Form A

Peak#	Chem Shift [ppm]	Intensity [rel]
I	173.5	38.2

554

Peak #	Chem Shift [ppm]	Intensity [rel]
2	164.7	8.8
3	162.1	12.9
4	142.9	29.0
5	142.3	38.2
6	137.6	25.4
7	136.5	21.6
8	132.8	37.1
9	131.8	81.1
10	130.8	100.0
11	127.9	35.4
12	122.1	30.1
13	118.6	30.6
14	116.8	23.4
15	112.8	28.1
16	98.2	26.9
17	95.0	35.4
18	67.4	53.6
19	66.7	48.7
20	35.9	65.3
21	30.8	39.5

(2) ’⁹F MAS Analysis

Solid state ^l9F NMR data for Compound 33 Fonn A îs provided in FIG. IC and summarized in Table 25 below.

Table 25: Solid State NMR of Compound 33 Form A

Peak #	Chem Shift [ppm]	Intensity [rel]
1	-109.3	12.5

D. Thermogravimctric Analysis

Thermal gravimétrie analysis of Compound 33 Form A was measured using the TA Instruments TGA Q5000. The thennogram showed 0.1% weight loss from ambient température up to 150°C. The TGA thermogram for Compound 33 Fonn A is provided in FIG. ID.

E. Differential Scanning Calorimetry Analysis

DSC of Compound 33 Form A was measured using the TA Instruments Q2000 DSC. The DSC thermogram is provided at FIG. IE and shows an endothennic peak at 346 JC.

F. IR Spectroscopy

The IR spectrum of Compound 33 Form A was collected using the Thenno Scientific Nicolet ÎS50 Spectrometer equipped with a diamond ATR sampling accessory. The IR spectrum of Compound 33 Fonn A is shown at FIG. 1F and the interprétation of the IR data is summarized in Table 26 below.

555

Table 26: Interprétation of IR Spectrum for Compound 33 Form A

-1 Frequency (cm )	Moiety	Vibration
3295	O-H	Stretch
3044	Aromatic C-H	Stretch
2956,2838	Aliphatic C-H	Stretch
1683	Acid C=O	Stretch
1610, 1510	Aromatic Ring C-C/C=C	Stretch
1223	Aromatic C-F	Stretch
935	Heteroaromatic Ring	Ring deformation

2. Compound 33 Form B

A. Synthetic Procedure:

15 mg of Compound 33 Fonn A was suspended in 0.3 mL DCM in a glass vial and stirred with a magnetic starring bar at RT for 3 days. The air dried solids were isolated as Compound 33 Form B.

B. X-Ray Powder Diffraction:

X-ray powder diffraction (XRPD) spectra were recorded at room température in 10 transmission mode using a PANalytical Empyrean system equipped with a sealed tube source and a PIXcel ID Medipix-3 detector (Malvcm PANalytical Inc, Westborough, Massachusetts). The X-Ray generator operated at a voltage of 45 kV and a current of 40 mA with copper radiation (L54060 Â). The powder sample was placed on a 96 well sample holder with mylar film and loaded into the instrument. The sample was scanned over the range of about 3° to about 15 40°20 7with a step size of 0.0131303° and 49s per step. The XRPD diffractogram is shown in

FIG. 2A and XRPD data are summarized in Table 27.

Table 27: XRPD Peaks for Compound 33 Form B

Peak #	Angle (Degrees 2-Theta ±0.2)	Intensity %
1	18.1	100.0
2	18.4	80.1
3	20.2	73.8
4	19.8	60.3
5	11.0	55.9
6	20.6	40.3
7	22.3	33.9
8	14.3	28.4
9	17.1	26.1
10	9.2	24.3
11	24.7	22.9
12	16.2	22.7
13	9.9	20.8

556

Peak #	Angle (Degrees 2-Theta ±0.2)	Intensîty %
14	4.5	20.6
15	28.9	15.5
16	12.7	14.5
17	15.1	12.8
18	16.8	11.8
19	21.4	11.6
20	27.4	10.6
21	23.6	10.4
22	26.6	10.3

C. Solid State NMR (1) ¹³C CPMAS Analysis

Solid state ¹³C NMR data for Compound 33 Fonn B is provided in FIG. 2B and 5 summarized in Table 28 below.

Table 28: Solid State NMR of Compound 33 Form B

Peak #	Chem Shift [ppm]	Intensîty [rel]
1	170.1	21.76
2	167.9	19.7
3	163.0	16.48
4	160.7	20.7
5	146.3	11.3
6	143.9	20.6
7	139.3	49.5
8	138.3	40.3
9	133.1	100.0
10	131.2	98.5
11	130.1	87.1
12	128.9	86.0
13	121.8	25.6
14	120.4	27.7
15	118.8	28.8
16	115.9	47.4
17	112.0	10.4
18	100.9	21.1
19	99.1	27.5
20	97.4	33.2
21	68.8	24.2
22	67.0	53.4
23	35.9	32.5
24	34.1	42.3
25	31.9	52.0

557 (2) ^l9F MAS Analysis

Solid state ^l9F NMR data for Compound 33 Form B îs provided in FIG. 2C and summarized in Table 29 below.

Table 29: Solid State NMR of Compound 33 Form B

Peak #	Chem Shift [ppm]	Intensîty [rel]
1	-110.2	9.9
2	-III.6	12.5
3	-115.6	2.76

D. Thermogravimetric Analysis

Thermal gravimétrie analysis of Compound 33 Form B was measured using TA Discovery 550 TGA from TA Instrument. A sample with weight of approximately 1-5 mg was scanned from 25 °C to 375 °C at a heating rate of 10 °C/min with nitrogen purge. Data were collected by Thermal Advantage Q Sériés™ software and analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The thermogram showed minimum weight loss from ambient température up to 250°C. The TGA thermogram for Compound 33 Form B is provided in FIG. 2D.

E. Differential Scanning Calorimetry Analysis:

DSC of Compound 33 Form B was measured using the TA Q2000 DSC from TA

Instrument. A sample with a weight between 1 and 10 mg was weighed into an aluminum pan. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed and a flow of nitrogen was passed through the cell. The heating program was set to heat the sample at a heating rate of 10° C/min to a température of 380° C. When the run was completed, the data were analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The thermogram showed an endothermie peak around 342 JC. The DSC thermogram is provided at FIG. 2E and shows an endothermie peak at 346ZlC.

3. Compound 33 DCM Solvaté Form A

A. Synthetic Procedure mg Compound 33 Form A was suspended in 1 ml solvent mixture of DCM, EtOH, and THF (54:36:10 by volume), and the vial was stirred with a magnetic stir bar at RT for one day. The solid was isolated as Compound 33 DCM solvaté Form A.

B. X-Ray Powder Diffraction:

The XRPD patterns are acquired at room température in reflection mode using a Bruker Advance equipped with Vantée-1 detector. Sample was analyzed on a Silicon sample holder from 3-40° 2-theta on continuons mode with step size of 0.0144531° and time per step of 0.25 558 seconds. Sample was spinning at 15 rpm. The XRPD diffractogram is shown in FIG. 3A and XRPD data are summarized in Table 30.

Table 30: XRPD Peaks for Compound 33 DCM Solvaté Form A

Peak#	Angle (Degrees 2-Theta ±0.2)	Relative Intensity %
1	20.9	100.0
2	18.3	87.8
3	14.4	59.5
4	17.2	59.4
5	20.3	43.2
6	22.8	28.3
7	22.6	24.1
8	27.7	23.9
9	8.8	23.3
10	7.1	23.3
11	28.3	21.6
12	9.0	18.8
13	26.6	17.4
14	10.1	14.7
15	13.9	14.3
16	23.4	12.9
17	27.1	12.3
18	13.3	11.7
19	21.7	10.7
20	24.0	10.0

C. Thermogravimetric Analysis

Thermal gravimétrie analysis of Compound 33 DCM solvaté Fonn A was measured using the TA Instruments TGA Q5000. A sample with weight of approximately 1-5 mg was scanned from 25 °C to 350 °C at a heating rate of 10 °C/min with nitrogen purge. Data were collected by Thermal Advantage Q Sériés™ software and analyzed by Trios and/or Universal 10 Analysis software (TA Instruments, New Castle, DE). The thermogram showed -7% weight loss from ambient temperature up to 175°C. The TGA thermogram for Compound 33 DCM solvaté Form A is provided in FIG. 3B.

D. Differential Scanning Calorimetry Analysis

DSC of Compound 33 DCM solvaté Form A was measured using the TA Instruments 15 Q2000 DSC. A sample with a weight between 1 and 10 mg was weighed into an aluminum pan.

This pan was placed in the sample position in the calorîmeter cell. An empty pan was placed in the reference position. The calorîmeter cell was closed and a flow of nitrogen was passed through the cell. The heating program was set to heat the sample at a heating rate of 2° C/mîn

559 (modulate ± 0.32 °C every 60 s) to a température of 350° C. When the run was completed, the data were analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The DSC thermogram is provided in FIG. 3C and shows an endothermie peak around 341 „C.

4. Compound 33 Hydrate Form A

A. Synthetic Procedure mg of Compound 33 Form A were weighed in 2 ml glass vial and 200-300 pl of water was added along with a small magnetic stir bar. The sample was stirred at RT for two weeks. Then the solid was isolated as Compound 33 hydrate Form A.

B. X-Ray Powder Diffraction

X-ray powder diffraction (XRPD) spectra were recorded at room température in transmission mode using a PANalytical Empyrean system equipped with a sealed tube source and a PIXcel ID Medipix-3 detector (Malvern PANalytical Inc, Westborough, Massachusetts). The X-Ray generator operated at a voltage of 45 kV and a current of 40 mA with copper radiation (l.54060 Â). The powder sample was placed on a 96 well sample holder with mylar film and loaded into the instrument. The sample was scanned over the range of about 3° to about 40°20 with a step size of 0.0131303° and 49s per step. The XRPD diffractogram is shown in FIG. 4A and XRPD data are summarized in Table 31.

Table 31: XRPD Peaks for Compound 33 Hydrate Form A

Peak #	Angle (Degrees 2-Theta ±0.2)	Relative Intensity %
1	19.5	100.0
2	10.4	79.9
3	16.6	32.7
4	13.6	25.6
5	18.4	24.4
6	21.6	20.8
7	17.5	18.9
8	21.1	17.6
9	18.9	17.6
10	21.8	12.3
11	20.8	11.5
12	24.8	10.5
13	21.4	10.1

C. Single Crystal Elucidation

Single crystals having the hydrate structure were grown from ethanol/water. X-ray diffraction data were acquired at 100K on a Bruker diffractometer equipped with Cu K_a radiation

560 (λ=1.54!78 Â) and a CMOS detector. The structure was solved and refined using SHELX programs (Sheldnck, G.M., Acta Cryst., (2008) A64, I12-122) and results are summarized in Table 32 below.

Table 32: Single crystal élucidation of Compound 33 hydrate Form A

Crystal System	Triclinic
Space Group	P-l
a (Â)	9.9750(16)
b (Â)	10.4232(8)
c(Â)	11.3003(5)
«(°)	74.060(6)
β(°)	78.914(7)
γ(°)	84.141(11)
V(Â3)	1107.1(2)
Z/Z'	2/1
T emperature	100 K

D. Solid State NMR (1) ¹³C CPMAS Analysis

Solid State ¹³C NMR data for Compound 33 hydrate Fonn A is provided in FIG. 4B and summarized in Table 33 below.

Table 33: Solid State NMR of Compound 33 Hydrate Form A

Peak #	Chem Shift [ppm]	Intensity [rel]
1	172.3	42.8
2	163.8	11.7
3	161.3	17.8
4	144.4	31.8
5	141.6	41.7
6	139.0	35.4
7	136.8	28.6
8	134.8	67.3
9	132.4	84.0
10	129.6	100.0
H	128.9	87.3
12	123.1	39.9
13	117.2	40.0
14	116.5	33.5
15	112.1	33.7
16	97.7	64.8
17	67.9	64.7
IS	36.1	4S.8
19	32.8	34.3
20	29.4	16.9
21	28.4	25.8

561 (2) ¹⁹F MAS Analysis

Solid State ^l9F NMR data for Compound 33 liydate Fonn A is provided in FIG, 4C and summarized in Table 34 below.

Table 34: Solid State NMR of Compound 33 Hydrate Form A

Peak#	Chem Shift [ppm]	Intensity [rel]
1	-103.1	12.5

E. Thermogravimetric Analysis

Thermal gravimétrie analysis of Compound 33 hydrate Form A was measured using the TA Instruments TGA Q5000. A sample with weight of approximately l-5 mg was scanned from 25 °C to 350 °C at a heating rate of 10 °C/min with nitrogen purge. Data were collected by Thermal Advantage Q Sériés™ software and analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The thermogram showed ~10 % weight loss from ambient température up to 60 °C. The TGA thermogram for Compound 33 hydrate Form A is provided in FIG. 4D.

F. Differential Scanning Calorimetry Analysis

DSC of Compound 33 hydrate Form A was measured using the TA Instruments Q2000 DSC. A sample with a weight between 1 and 10 mg was weighed into an aluminum pan. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed and a flow of nitrogen was passed through the cell. The heating program was set to heat the sample at a heating rate of 10° C/min to a température of 360° C. When the run was completed, the data were analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The DSC thermogram provided in FIG, 4E shows two endothermie peaks around 89 and 342 JC.

5. Compound 33 MeOH/H₂O Solvate/Hydrate Form A

A group of Compound 33 isostructural MeOH/H₂O sol vate/hyd rate with different API/solvent/water ratios, one of which has a similar PXRD pattern as the MeOH/H₂O solvaté.

A. Synthetic Procedure mg of Compound 33 Form A were weighed in 2 ml glass vial and 200-300 μΐ of MeOH was added along with a small magnetic stir bar. The sample was stirred at RT for two weeks. Then the solid was isolated as Compound MeOH/FHO Solvate/Hydrate Fonn A.

B. X-Ray Powder Diffraction

X-ray powder diffraction (XRPD) spectra were recorded at room température in transmission mode using a PANalytical Empyrean system equipped with a sealed tube source and a PIXcel ID Medîpix-3 detector (Malvem PANalytical Inc, Westborough, Massachusetts).

562

The X-Ray generator operated at a voltage of 45 kV and a current of 40 mA with copper radiation (1.54060 Â). The powder sample was placed on a 96 well sample holder with mylar film and loaded into the instrument. The sample was scanned over the range of about 3° to about 40°2Θ with a step size of 0.0131303° and 49s per step. The XRPD diffractogram is shown in 5 FIG. 5A and XRPD data are summarized in Table 35.

Table 35: XRPD Peaks for Compound 33 MeOH/HîO Solvate/Hydrate Form A

Peak #	Angle (Degrees 2-Theta ±0.2)	Relative Intensity %
1	19.4	100.0
2	10.4	55.6
3	18.2	28.7
4	16.6	25.0
5	13.5	20.2
6	21.0	19.1
7	21.6	18.1
8	18.8	17.9
9	17.4	13.0
10	21.3	10.0
11	21.7	10.7
12	24.0	10.0

C. Single Crystal Elucidation

Single crystals having the MeOH/H₂O structure were grown from methanol. X-ray diffraction data were acquired at 100K on a Bruker diffractometer equipped with Cu K_CI radiation (λ=1.54178 Â) and a CMOS detector. Tire structure was solved and refined using SHELX programs (Sheldrick, G.M., Acta Cryst., (2008) A64, 112-122) and results are summarized in Table 36 below.

Table 36: Single crystal élucidation of Compound 33 MeOH/H₂O Solvate/Hydrate

Form A

Crystal System	Triclinic
Space Group	P-l
a(Â)	10.0229(3)
b(Â)	10.4254(3)
c(Â)	11.2467(4)
a(°)	74.4963(9)
β(°)	79.6241(9)
γ(°)	84.9826(9)
V(ÂJ)	1112.96(6)
Z/Z'	2/1
T emperature	100 K

563

D. Thermogravimetric Analysis

Thennal gravimétrie analysis of Compound 33 MeOH/H₂O Solvate/Hydrate Form A was measured using the TA Instruments TGA Q5000. A sample with weight of approximately 1-5 mg was scanned from 25 °C to 350 °C at a heating rate of 10 °C/min with nitrogen purge. Data were collected by Thermal Advantage Q Sériés™ software and analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The TGA thermogram as provided in FIG. 5B shows 3.3 % weight loss from ambient température up to 150 °C.

E. Differential Scannîng Calorimetry Analysis

DSC of Compound 33 MeOH/H₂O Solvate/Hydrate Form A was measured using the TA Instruments Q2000 DSC. A sample with a weight between 1 and 10 mg was weighed into an aluminum pan. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed and a flow of nitrogen was passed through the cell. The heating program was set to heat the sample at a heating rate of 10° C/min to a température of 357° C. When the run was completed, the data were analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The DSC thermogram as provided in FIG. 5C shows two endothermie peaks around 111 and 348 üC.

6. Compound 33 Form C

A. Synthetic Procedure

210.9 mg of Compound 33 Form A was weighed and dissolved in 42 mL of MeOH, after the sample was warmed to 45 °C for 10 min followed by 50 ^ÜC for 5 minutes. It was used as the stock solution after cooling to room température. Compound 33 was stirred in MeOH/water at 2/1 (vol.), prepared by mixing 6 mL of stock solution and 3 mL water, at 45°C for 3 days. Then the solid was isolated as Compound 33 Form C.

B. X-Ray Powder Diffraction

X-ray powder diffraction (XRPD) spectra were recorded at room température in transmission mode using a PANalytical Empyrean system equipped with a sealed tube source and a PIXcel ID Medipix-3 detector (Malvern PANalytical Inc, Westborough, Massachusetts). The X-Ray generator opérâted at a voltage of 45 kV and a carrent of 40 mA with copper radiation (1.54060 Â). The powder sample was placed on a 96 well sample holder with mylar film and loaded into the instrument. The sample was scanned over the range of about 3° to about 40°2θ with a step size of 0.0131303° and 49s per step. The XRPD diffractogram is shown in FIG. 6A and XRPD data are summarized in Table 37.

564

Table 37: XRPD Peaks for Compound 33 Form C

Peak #	Angle (Degrees 2-Theta ±0.2)	Relative Intensity %
l	19.0	100.0
2	2L0	42.4
3	9.4	20.2
4	18.2	15.4
5	15.4	15.3
6	21.5	14.8
7	20.2	14.5
8	19.6	10.5

7. Compound 33 Form D

A. Synthetic Procedure

Approximately 15 mg of Compound 33 THF solvaté Form A was weighed into a 4-mL vial, which was placed into a 20-mL vial with 2 mL of MeOH. The 20-mL vial was sealed with a cap and kept at RT for ten days allowing solvent vapor to interact with the solid sample. Then the solid was taken out as Compound 33 Fonn D.

B. X-Ray Powder Diffraction

XRPD was perfonned with a Panalytical X’Pert³ Powder XRPD on a Si zero-background holder. The 20 position was calibrated against a Panalytical Si reference standard dise. The parameters used are listed in the Table 38. The XRPD diffractogram is shown in FIG. 7A and XRPD data are summarized in Table 39.

Table 38: Parameters for XRPD test of Compound 33 Form D

Parameters	Rcnection Mode
	Cu, ka
X-Ray wavelength	Καί (Â): 1.540598, Ka2 (Â): 1.544426,
	Κα2/Κα1 intensity ratio: 0.50
X-Ray tube setting	45 kV, 40 mA
Divergence slit	Fixed 1/8°
Scan mode	Continuous
Scan range	3-40
(° 2TH)
Scan step time [s]	18.87
Step size (° 2TH)	0.0131
Test Time	4 min 15 s

Table 39: XRPD Peaks for Compound 33 Form D

565

Peak #	Angle (Degrees 2-Theta ±0.2)	Relative Intensity %
1	10.4	100.0
2	20.5	75.3
3	14.4	54.1
4	20.1	51.1
5	7.8	39.9
6	8.2	34.5
7	8.6	26.3
8	15.3	25.1
9	24.0	18.5
10	18.9	17.6
11	24.3	17.1
12	18.6	15.6
13	13.7	15.5
14	21.9	12.9

C. Thermogravimetric Analysis

Thermal gravimétrie analysis of Compound 33 Fonn D was measured using TA Discovery 550 TGA from TA Instrument. A sample with weight of approximately 1-5 mg was scanned from 25 °C to 290 °C at a heating rate of 10 °C/min with nitrogen purge. Data were collected by Thermal Advantage Q Sériés™ software and analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The TGA thennogram as provided in FIG. 7B shows around 5 % weight loss from ambient température up to around 220°C.

D. Differential Scanning Calorimetry Analysis

DSC of Compound 33 Form D was measured using the TA Q2000 DSC from TA Instrument. A sample with a weight between 1 and 10 mg was weighed into an aluminum pan. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed and a flow of nitrogen was passed through the cell. The heating program was set to heat the sample at a heating rate of 10° C/min to a température of 300° C. When the run was completed, the data were analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The DSC thermogram in FIG. 7C shows multiple exothermic and endothermie peaks around 162, 240, and 250 üC.

8. Compound 33 Form E

A. Synthetic Procedure

210.9 mg of Compound 33 Form A was weighed and dissolved in 42 mL of MeOH, after the sample was warmed to 45 °C for 10 min followed by 50 °C for 5 minutes. It was used as the stock solution after cooling to room température. 6 mL of the stock solution was moved to the cold room and stirred for 3 days. Then the solid was isolated as Compound 33 Form E.

566

B. X-Ray Powder Diffraction

X-ray powder diffraction (XRPD) spectra were recorded at room température in transmission mode using a PANalytical Empyrean system equipped with a sealed tube source and a PIXcel ID Medipix-3 detector (Malvem PANalytical Inc, Westborough, Massachusetts).

The X-Ray generator operated at a voltage of 45 kV and a current of 40 mA with copper radiation (1.54060 Â). The powder sample was placed on a 96 well sample holder with mylar film and loaded into the instrument. The sample was scanned over the range of about 3° to about 40°2θ with a step size of 0.0131303° and 49s per step. . The XRPD diffractogram is shown in FIG. SA and XRPD data are summarized in Table 40.

Table 40: XRPD Peaks for Compound 33 Form E

Peak#	Angle (Degrees 2-Theta ±0.2)	Relative Intensity %
1	20.7	100.0
2	12.6	65.2
3	17.9	46.6
4	11.2	45.0
5	7.9	42.7
6	16.2	31.2
7	22.8	24.9
8	21.1	24.4
9	12.8	21.2
10	19.9	19.1
11	13.7	19.0
12	27.0	16.3
13	22.5	15.1
14	15.3	14.5
15	28.9	13.1
16	25.0	12.9
17	24.1	11.1

9. Compound 33 Form F

A. Synthetic Procedure

0.2 g Compound A THF solvaté Form A and 2 ml of EtOH were added in a vial with a 15 magnetic stir bar, and slurrifying at 20 °C for overnight. Then the solid was isolated as Compound 33 Form F.

B. X-Ray Powder Diffraction

X-ray powder diffraction (XRPD) spectra were recorded at room température in transmission mode using a PANalytical Empyrean system equipped with a sealed tube source 20 and a PIXcel ID Medipix-3 detector (Malvem PANalytical Inc, Westborough, Massachusetts).

567

The X-Ray generator operated at a voltage of 45 kV and a current of 40 mA with copper radiation (l.54060 Â). The powder sample was placed on a 96 well sample holder with mylar film and loaded into the instrument. The sample was scanned over the range of about 3° to about 40°2θ with a step size of 0.0131303° and 49s per step. The XRPD diffractogram is shown in 5 FIG. 9A and XRPD data are summarized în Table 41.

Table 41: XRPD Peaks for Compound 33 Form F

Peak #	Angle (Degrees 2-Theta ±0.2)	Relative Intensity %
1	19.2	100.0
2	18.4	84.7
3	15.1	40.6
4	18.3	37.6
5	22.8	37.5
6	11.6	35.6
7	17.8	33.5
8	21.4	28.1
9	24.9	23.7
10	23.0	21.9
11	14.2	21.2
12	19.0	20.5
13	14.9	19.4
14	20.4	17.0
15	12.2	16.9
16	23.3	14.3
17	8.6	13.4
18	21.6	12.6
19	13.0	12.5
20	25.8	12.2
21	17.4	12.1
22	17.3	11.9
23	11.4	11.8
24	26.4	11.0
25	7.7	11.0
26	24.0	10.9
27	24.2	10.8
28	22.6	10.6

C. Thermogravimetric Analysis

Thermal gravimétrie analysis of Compound 33 Form F was measured using TA

Discovery TGA from TA Instrument. A sample with weight of approximately 1-10 mg was scanned from 25 °C to 300 °C at a heating rate of 10 °C/min with nitrogen purge. Data were collected by Thermal Advantage Q Sériés™ software and analyzed by Trios and/or Universal

568

Analysis software (TA Instruments, New Castle, DE). The TSC thermogram of FIG. 9B shows 7.4 % weight loss from ambient température up to 200°C.

D. Differential Scanning Calorîmetry Analysis

DSC of Compound 33 Fonn F was measured using the TA Discovery DSC from TA Instrument. A sample with a weight between l-5 mg was weighed into an aluminum pan. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed and a flow of nitrogen was passed through the cell. The heatîng program was set to heat the sample at a heatîng rate of 10 °C/min to a température of 300 °C. When the run was completed, the data were analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The DSC thennogram provided in FIG. 9C shows an endothermie peak around 147 üC and an exothermic peak around 174 üC. 10. Compound 33 Form G

A. Synthetic Procedure

About 20 mg of Compound 33 Fonn A was suspended in 0.2 mL of EtOH in a 2-mL glass vial, and the siurry was stirred magnetically for one day at 5 °C. Then the solids were isolated as Compound 33 Fonn G.

B. X-Ray Powder Diffraction

XRPD was perfonned with a Panalytical X’Pert³ Powder XRPD on a Si zero-background holder. The 20 position was calibrated against a Panalytical Si reference standard dise. The parameters used are listed in the Table 42. The XRPD diffractogram is shown in FIG. 10A and XRPD data are summarized in Table 43.

Table 42: Parameters for XRPD test of Compound 33 Form G

Parameters	Reflection Mode
	Cu, ka
X-Ray wavelength	Kal (Â): 1.540598, Ka2 (Â): 1.544426,
	Ka2/Kal intensity ratio: 0.50
X-Ray tube setting	45 kV, 40 mA
Divergence slit	Fixed 1/8°
Scan mode	Continuous
Scan range (° 2TH)	3-40
Scan step time [s]	18.87
Step size (° 2TH)	0.0131
Test Time	4 min 15 s

Table 43: XRPD Peaks for Compound 33 Form G

569

Peak #	Angle (Degrees 2-Theta ±0.2)	Relative Intensity %
ï	20.2	100.0
2	19.8	67.7
3	20.8	52.4
4	9.3	40.1
5	10.8	35.8
6	24.2	35.6
7	21.6	32.6
8	18.4	27.0
9	11.5	20.5
10	23.4	16.3
11	22.6	15.3
12	19.1	14.9
13	17.5	14.8
14	12.6	11.4
15	25.5	10.9

C. Thermogravimetric Analysis

Thennal gravimétrie analysis of Compound 33 Form G was measured using TA Discovery 550 TGA from TA Instrument, A sample with weight of approximately l-5 mg was scanned from 25 °C to 290 °C at a heating rate of 10 °C/min with nitrogen purge. Data were collected by Thermal Advantage Q Sériés™ software and analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The TSC thennogram provided in FIG. 10B shows 3 % weight loss from ambient température up to 75 °C and another 3 % weight loss from 75 to 180 °C.

D. Differential Scanning Calorimetry Analysis

DSC of Compound 33 Form G was measured using the TA Q2000 DSC from TA Instrument. A sample with a weight between l -10 mg was wetghed into an aluminum pan. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed and a flow of nitrogen was passed through the cell. The heating program was set to heat the sample at a heating rate of 10° C/min to a température of 250° C. When the run was completed, the data were analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The DSC thermogram provided in FIG. 10C shows endothermie peaks around 86 and 205 JC.

11. Compound 33 Form H

A. Synthetic Procedure

Approximately 15 mg of Compound 33 Form A was dissolved in 0.1-0.2 mL EtOH to obtain a clear solution in a 3-mL vial. This solution was then placed into a 20-mL vial with 3 mL

570 of water. The 20-mL vial was sealed with a cap and kept at RT allowing enough time for the water vapor to internet with the solution. The précipitâtes were isolated as Compond 33 Form H.

B. X-Ray Powder Diffraction

XRPD was perfonned with a Panalytical X’Pert³ Powder XRPD on a Si zero-background holder. The 2Θ position was calibrated against a Panalytical Si reference standard dise. The parameters used are lîsted in the Table 44. The XRPD diffractogram is shown in FIG. 11A and XRPD data are summarized in Table 45.

Table 44: Parameters for XRPD test of Compound 33 Form H

Parameters	Reflection Mode
X-Ray wavelength	Cu, ka Καί (Â): 1.540598,
Ka2 (Â): 1.544426, Κα2/Κα1 intensity ratio: 0.50
X-Ray tube setting	45 kV, 40 mA
Divergence slit	Fixed 1/8°
Scan mode	Continuous
Scan range	3-40
(° 2TH)
Scan step time [s]	18.87
Step size	0.0131
(° 2TH)
Test Time	4 min 15 s

Table 45: XRPD Pcaks for Compound 33 Form H

Peak #	Angle (Degrees 2-Theta ±0.2)	Relative Intensity %
1	5.0	100.0
2	19.5	86.2
3	18.3	36.8
4	18.9	20.6
5	20.7	13.2
6	15.0	10.8
7	17.6	10.7
8	8.8	10.3

C. Therinogravimetric Analysis

Thermal gravimétrie analysis of Compound 33 Form H was measured using TA Discovery 550 TGA from TA Instrument. A sample with weight of approximately 1-5 mg was 15 scanned from 25 °C to 290 °C at a heating rate of 10 °C/min with nitrogen purge. Data were collected by Thermal Advantage Q Sériés™ software and analyzed by Trios and/or Universal

571

Analysis software (TA Instruments, New Castle, DE). The TGA thermogram provided in FIG. 1 IB shows 1.6 % weight loss from ambient température up to 150°C.

D. Differential Scanning Calorimetry Analysis

DSC of Compound 33 Form H was measured using the TA Q2000 DSC from TA Instrument. A sample with a weight between 1-10 mg was weighed into an aluminum pan. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed and a flow of nitrogen was passed through the cell. The heating program was set to heat the sample at a heating rate of 10° C/min to a température of 300° C. When the run was completed, the data were analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The DSC thermogram provided in FIG. 11C shows an endothermie peak around 135 JC.

12. Compound 33 Form I

A. Synthetic Procedure

The solid form was observed after the distillative crystallization of raw Compound 33 from 2 Me-THF/THF to EtOH/water. Specifically, EtOH-reacted Compound 33 (see FIG. 12A for XRPD diffractogram and Table 46 for XRPD diffraction data) was initially sampled after adding 50 ml of EtOH, which was previously washed by water followed by 2 cycles of adding 50 ml EtOH and distillation. After Compound 33 was added with 100 ml of EtOH/water (3:1) and stirred at ambient température overnight, the crude product (see FIG. 12B for XRPD diffractogram and Table 47 for XRPD diffraction data) sampled was a wet cake. Compound 33 Form I was the solid after drying in vacuum oven with nitrogen bleed at 66 °C overnight (see FIG. 12C for XRPD diffractogram and Table 48 for XRPD diffraction data).

B. X-Ray Powder Diffraction

X-ray powder diffraction (XRPD) spectra were recorded at room température in transmission mode using a PANalytical Empyrean system equipped with a sealed tube source and a PIXcel ID Medipix-3 detector (Malvem PANalytical Inc, Westborough, Massachusetts). The X-Ray generator operated at a voltage of 45 kV and a current of 40 mA with copper radiation (1.54060 Â). The powder sample was placed on a 96 well sample holder with mylar film and loaded into the instrument. The sample was scanned over the range of about 3° to about 4O°20 with a step size of 0.0131303° and 49s per step.

572

Table 46: XRPD Peaks for EtOH-Reacted Compound 33 (Initial Sampling)

Peak #	Angle (Degrees 2-Theta ±0.2)	Relative Intensity %
l	19.6	100.0
2	20.2	67.9
3	19.2	63.9
4	10.6	49.1
5	17.1	47.7
6	9.7	29.7
7	12.8	22.9
8	20.8	20.8
9	11.1	20.0
10	18.5	19.4
11	23.3	13.7
12	13.8	10.5

Table 47: XRPD Peaks for Compound 33 Reacted with EtOH Ovenight

Peak #	Angle (Degrees 2-Theta ±0.2)	Relative Intensity %
1	4.9	100.0
2	19.1	75.0
3	19.0	62.2
4	18.5	55.9
5	20.1	45.3
6	18.7	42.9
7	20.4	42.4
8	19.4	34.2
9	9.7	31.4
10	17.0	28.2
11	12.0	21.2
12	21.0	18.4
13	22.7	18.4
14	15.6	14.0
15	21.9	13.6
16	13.9	12.1
17	10.5	11.6
18	21.5	11.1
19	14.2	10.9
20	9.3	10.8
1 21	14.8	10.7

Table 48: XRPD Peaks for Compound 33 Form I

Peak #

Angle (Degrees 2-Theta ±0.2)

Relative Intensity %

573

Peak #	Angle (Degrees 2-Theta ±0.2)	Relative Intensîty %
1	19.0	100.0
2	9.3	19.2
3	21.0	15.9
4	18.3	13.8
5	20.2	13.6
6	15.4	13.3
7	18.6	10.8

C. Thermogravimetric Analysis

Thennal gravimétrie analysis of Compound 33 Form I was measured using the TA Instruments TGA Q5000. A sample with weight of approximately 1-5 mg was scanncd from 25 °C to 350 °C at a heating rate of 10 °C/min with nitrogen purge. Data were collected by Thermal Advantage Q Sériés^{1 M} software and analyzed b y Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The TGA thennogram provided in FIG. 12D showed 9.4 % weight loss from ambient température up to 230 °C and another 6.0 % weight loss from 230 to 350 °C.

D. Differentiai Scanning Calorimetry Analysis:

DSC of Compound 33 Form J was measured using the TA Instruments Q2000 DSC. A sample with a weight between 1-10 mg was weighed into an aluminum pan. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed and a flow of nitrogen was passed through the cell. The heating program was set to heat the sample at a heating rate of 2° C/min (modulate ± 0.32 °C every 60 s) to a température of 350° C. When the run was completed, the data were analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The DSC thermogram în FIG. 12E shows two endothermie peaks around 200 and 283 JC.

13. Compound 33 THF Solvaté Form A

A. Synthetic Procedure:

Compound 33 Form A (10.4 g, 22.833 mmol, 1 equiv.) was dissolved in THF/H2O 9:1 (100.4 mL, 10 Vols) and the reaction mixture was heated to 60 °C. Water (18.72 mL, 1.8 Vols) was added the the heating at 60°C was continued for over 15 minutes. The reaction was cooled down to 53 °C. The reaction was further cooled down to 20 °C and water (74.88 mL, 7.2 Vols) was at 20 °C over 1 hour. The reaction mixture was then stirred for another hour. The product was isolated by filtration and dried in vacuum oven at 64 °C with nitrogen bleed. Compound 33 THF Solvaté Form A was isolated în 95% yield. Exemplary alternative solvent combinations to

574 make the Compound 33 THF Solvaté Form A include THF/Water 9: l vol/vol with 20 vol IPA, THF/Water 9:10.5 vol/vol with 1 vol MeOH, and THF/Water 10:9.5 vol/vol with 0.1 vol IPA.

Alternatively, 10 mg of Compound 33 Fonn A can be weighed in 2 ml glass vial and 200-300 μΐ of THF added along with a small magnetic stir bar. The sample is stirred at RT for two weeks. Then the solid can be isolated as Compound 33 THF Solvaté Fonn A.

B. X-Ray Powder Diffraction

X-ray powder diffraction (XRPD) spectra were recorded at room température in transmission mode using a PANalytical Empyrean system equipped with a sealed tube source and a PIXcel ID Medipix-3 detector (Malveni PANalytical Inc, Westborough, Massachusetts). The X-Ray generator opérâted at a voltage of 45 kV and a current of 40 mA with copper radiation (1.54060 Â). The powder sample was placed on a 96 well sample holder with mylar film and loaded into the instrument. The sample was scanned over the range of about 3° to about 40° 20 with a step size of 0.0131303° and 49s per step. . The XRPD diffractogram is shown în FIG. 13A and XRPD data are summarized in Table 49.

Table 49: XRPD Peaks for Compound 33 THF Solvaté Form A

Peak #	Angle (Degrees 2-Theta ±0.2)	Relative Intensity %
1	19.4	100.0
2	19.1	58.0
3	21.5	37.4
4	8.5	23.7
5	11.3	18.4
6	20.5	17.2
7	21.2	15.1
8	17.1	14.9
9	9.5	14.7
10	21.1	13.8
II	23.1	12.6
12	22.9	12.3
13	8.2	10.9
14	17.8	10.4

C. Single Crystal Elucidation

Single crystals having the THF solvaté structure were grown from ethanol/water. X-ray diffraction data were acquired at 10ÛK on a Bruker diffractometer equipped with Cu K_a radiation (λ= 1.54178 Â) and a CMOS detector. The structure was solved and refined using SHELX programs (Sheldrick, G.M., Acta Cryst., (2008) A64, 112-122) and results are summarized in Table 50 below.

575

Table 50: Single crystal élucidation of Compound 33 THF solvaté Form A

Crystal System	Orthorhombic
Space Group
a(Â)	25.1154(5)
b(Â)	11.9769(2)
c(Â)	17.7368(4)
a(°)	90
β(°)	90
γ(°)	90
V(Â3)	5335.31
Z/Z'	4/2
Température	100 K

D. Solid State NMR (1) ¹³C CPMAS Analysis

Solid State ¹³C NMR data for Compound 33 THF solvaté Form A is provided in FIG. 13B and summarized in Table 51 below.

Table 51: Solid State NMR of Compound 33 Solvaté Form A

Peak #	Chem Shift [ppm]	Intensity [rel]
1	167.2	25.2
2	165.8	20.5
3	163.1	12.6
4	160.7	22.7
5	144.5	29.2
6	140.0	20.7
7	138.5	20.8
S	137.2	48.6
9	133.9	100.0
10	131.7	50.5
11	129.4	82.4
12	121.2	46.9
13	117.9	19.6
14	115.6	22.0
15	114.3	36.9
16	113.3	24.4
17	99.3	29.4
18	98.5	29.3
19	96.5	22.6
20	96.1	23.0
21	69.0	95.8
22	68.0	96.8
23	35.7	47.2
24	31.1	13.8
25	29.8	15.9
26	25.7	82.3

576

Peak#	Chem Shift [ppm]	Intensity [rel]
27	25.3	87.5

(2) ¹⁹F MAS Analysis

Solid state ^l9F NMR data for Compound 33 THF solvaté Form A is provided in FIG. 13C and summarized in Table 52 below.

Table 52: Solid State NMR of Compound 33 THF Solvaté Form A

Peak#	Chem Shift [ppm]	Intensity [rel]
I	-110.5	12.5
2	-113.0	6.8

E. Thermogravimetric Analysis

Thermal gravimétrie analysis of Compound 33 THF solvaté Fonn A was measured using the TA Instruments TGA Q5000. A sample with weight of approximately l-5 mg was scanned from 25 °C to 350 °C at a heating rate of 10 °C/min with nitrogen purge. Data were collected by Thermal Advantage Q Sériés™ software and analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The TGA thermogram as provided in FIG. 13D shows 13.4 % weight loss from ambient température up to 170 °C.

F. Différentiel Scanning Calorimetry Analysis

DSC of Compound 33 THF solvaté Fonn A was measured using the TA Instruments Q2Û00 DSC. A sample with a weight between 1 andlO mg was weighed into an aluminum pan. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed and a flow of nitrogen was passed through the cell. The heating program was set to heat the sample at a heating rate of 10° C/mîn to a température of 360° C. When the run was completed, the data were analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The DSC thermogram as provided in FIG. 13E shows two endothermie peaks around 161 and 347 JC.

14. Compound 33 Form J

A. Synthetic Procedure ~ 16.2 mg of Compound 33 Form A was weighed into a 3-mL glass vial. Then the 0.5 mL solvent, THF:EtOH:Water 6:1:1 (v/v/v), was added to get a saturated solution at RT. This sample was slurried for l hour and was then filtered using a Nylon membrane with the pore size of 0.22 pm into a new vial. Then - 2 mg of a pre-prepared polymer mixture (polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinylchloride (PVC), hypromellose (HPMC), methyl cellulose (MC) (mass ratio of 1:1:1:1:1)) was added into the filtrate and stirred at RT to induce précipitation for a day. No précipitation occurred, so the clear solution was then

577 transferred to slow évaporation (vial covered with parafilm that had a hole poked through it) to induce précipitation. The precipitated solid was isolated as Compound 33 Fonn J.

B. X-Ray Powder Diffraction

XRPD was performed with a Panalytical X’Perf Powder XRPD on a Si zéro-background 5 holder. The 2Θ position was calibrated against a Panalytical Si reference standard dise. The parameters used are listed in the Table 53. The XRPD diffractogram is shown in FIG. 14A and XRPD data are summarized in Table 54.

Table 53: Parameters for XRPD test of Compound 33 Form J

Parameters	Reflection Mode
	Cu, ka
X-Ray wavelength	Καί (Â): 1.540598, Ka2(Â): l.544426, Ka2/Kal intensity ratio: 0.50
X-Ray tube setting Divergence slit Scan mode Scan range (° 2TH) Scan step time [s] Step size (° 2TH) Test Time	45 kV, 40 mA Fixed 1/8° Continuous 3-40 18.87 0.0131 4 min 15 s

Table 54: XRPD Peaks for Compound 33 Form J

Peak #	Angle (Degrees 2-Theta ±0.2)	Relative Intensity %
1	6.6	100.0
2	15.0	77.0
3	19.4	74.8
4	10.3	55.8
5	16.0	44.3
6	19.9	41.2
7	16.8	39.2
8	20.6	35.3
9	20.8	27.4
10	15.6	20.6
11	21.4	19.7
12	22.5	16.1
13	7.5	15.6
14	20.1	14.0
15	21.7	12.0
16	17.9	11.0

578

C. Thermogravimetric Analysis

Thennal gravimétrie analysis of Compound 33 Fonn J was measured using TA Discovery 550 TGA from TA Instrument. A sample with weight of approximately l-5 mg was scanned from 25 °C to 290 °C at a heating rate of 10 °C/min with nitrogen purge. Data were collected by Thermal Advantage Q Sériés™ software and analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The TGA thermogram as provided in FIG. 14B shows 20.3 % weight loss from ambient température up to IS0°C.

15. Compound 33 Form K

A. Synthetic Procedure

Approximately 15 mg of Compound 33 Form A was dissolved in 0,1-0.2 mL THF to obtain a clear solution in a 3-mL vial. This solution was then placed into a 20-mL vial with 3 mL of water. The 20-mL vial was sealed with a cap and kept at RT allowing enough time for the water vapor to interact with the solution. The precipitate was isolated for as Compound 33 Form K.

B. X-Ray Pow der Diffraction

XRPD was perfonned with a Panalytical X’Perf Powder XRPD on a Si zero-background holder. The 20 position was calibrated against a Panalytical Si reference standard dise. The parameters used are listed in the Table 55. The XRPD diffractogram is shown in FIG. ISA and XRPD data are summarized in Table 56.

Table 55: Parameters for XRPD test of Compound 33 Form K

Parameters	Reflection Mode
	Cu, ka
X-Ray wavelength	Καί (Â): 1.540598, Ka2(Â): 1.544426,
	Κα2/Κα1 intensity ratio: 0.50
X-Ray tube setting	45 kV, 40 mA
Divergence slit	Fixed 1/8°
Scan mode	Continuous
Scan range (° 2TH)	3-40
Scan step time [s]	18.87
Step size (° 2TH)	0.0131
Test Time	4 min 15s

Table 56: XRPD Peaks for Compound 33 Form K

Peak #Angle (Degrees 2-Theta ±0.2) j Relative

579

		Intensity %
1	9.7	100.0
2	20.5	68.2
3	19.7	59.2
4	19.4	58.1
5	19.1	45.9
6	11.2	26.1
7	21.0	23.7
8	17.0	20.0
9	14.5	19.0
10	24.4	12.6

C. Thermogravimetric Analysis

Thermal gravimétrie analysis of Compound 33 THF Form K was measured using TA Discovery 550 TGA from TA Instrument. A sample with weight of approximately l-5 mg was scanned from 25 °C to 290 °C at a heating rate of 10 °C/min with nitrogen purge. Data were collected by Thermal Advantage Q Sériés™ software and analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The TGA thermogram as provided in FIG. 15B shows 5.8 % weight loss from ambient temperature up to 100°C and additional 14.8% weight loss from 100 °C up to 290 °C.

D. Differential Scanning Calorimetry Analysis

DSC of Compound 33 Form K was measured using the TA Q2000 DSC from TA Instrument. A sample with a weight between 1-10 mg was weighed into an aluminum pan. This pan was placed in the sample position in the calorîmeter cell. An empty pan was placed în the reference position. The calorîmeter cell was closed and a flow of nitrogen was passed through the cell. The heating program was set to heat the sample at a heating rate of 10° C/min to around temperature of 300° C. When the run was completed, the data were analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The DSC thermogram as provided in FIG. 15C shows an exothennic peak around 116 JC and endothermie peak around 156 JC.

16. Compound 33 2-MeTHF Solvaté Form A

A. Synthetic Procedure

About 20 mg of Compound 33 Fonn A was suspended in 0.2 mL of 2-MeTHF in a 2-mL glass vial, and the slurry was stirred magnetically for two days at RT or one day at 5 °C. Then the solids were isolated as Compound 33 2-MeTHF Solvaté Form A.

580

B. X-Ray Powder Diffraction

XRPD was performed with a Panalytical X’Pert Powder XRPD on a Si zero-background holder. The 20 position was calibrated against a Panalytical Si reference standard dise. The parameters used are listed in the Table 57. The XRPD diffractogram is shown in FIG. 16A and 5 XRPD data are summarized in Table 58.

Table 57: Parameters for XRPD test of Compound 33 2-MeTHF Solvaté Form A

Parameters	Reflection Mode
X-Ray wavelength X-Ray tube setting	Cu, ka Kal (Â): l.540598, Ka2 (Â): 1.544426, Ka2/Kal intensity ratio: 0.50 45 kV, 40 mA
Divergence slit	Fixed I/8°
Scan mode	Continuous
Scan range (° 2TH) Scan step time [s]	3-40 18.87
Step size (° 2TH) Test Time	0.0131 4 min 15s

Table 58: XRPD Peaks for Compound 33 2-MeTHF Solvaté Form A

Peak #	Angle (Degrees 2-Theta ±0.2)	Relative Intensity %
1	18.1	100.0
2	19.0	24.3
3	21.3	22.6
4	20.8	13.3
5	20.0	13.0
6	18.7	12.2
7	13.8	10.4

C. Thermogravimetric Analysis

Thermal gravimétrie analysis of Compound 33 2-MeTHF Solvaté Form A was measured using the TA Instruments TGA Q5Û00. A sample with weight of approximately l-5 mg was scaimed from 25 °C to 350 °C at a heating rate of 10 °C/min with nitrogen purge. Data were collected by Thermal Advantage Q Sériés™ software and analyzed by Trios and/or Universal

581

Analysis software (TA Instruments, New Castle, DE). The TGA thermogram provided in FIG. 16B shows 15% weight loss from ambient température up to 160 °C.

D. Differential Scanning Calorimetry Analysis

DSC of Compound 33 2-MeTHF Solvaté Form A was measured using the TA Instruments Q2000 DSC. A sample with a weight between 1-5 mg was weighed into an aluminum pan. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed and a flow of nitrogen was passed through the cell. The heatîng program was set to heat the sample at a heatîng rate of 10° C/min to around 357° C. When the run was completed, the data were analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The DSC thermogram provided in FIG. 16C shows two endothermie peaks around 130 and 346 ÜC.

17. Compound 33 Form L

A. Synthetic Procedure

Approximately 15 mg of Compound 33 Form A was dissolved in 1-2 mL of 2-MeTHF in a 3-mL glass vial. The visually clear solution was allowed a slow évaporation at RT. The solids were isolated as Compound 33 Fonn L.

In an alternative procedure, approximate 15 mg of Compound 33 Fonn A was added with 0.2 mL of 2-MeTHF/Heptane (1:1, v:v). The mixture was then heated to 50 °C with magnetic stirring and equilibrated for two hours, and then filtered using a PTFE membrane (pore size of 0.20 pm). The filtrate was slowly cooled down to 5 °C at a rate of 0.1 °C/min, and the precîpitated solids were isolated as Compound 33 Form L.

B. X-Ray Powder Diffraction

XRPD was perfonned with a Panalytical X’Pert³ Powder XRPD on a Si zero-background holder. The 2Θ position was calibrated against a Panalytical Si reference standard dise. The parameters used are listed in the Table 59. The XRPD diffractogram is shown in FIG. 17A and XRPD data are summarized in Table 60.

582

Table 59: Parameters for XRPD test of Compound 33 2-MeTHF solvaté Form A

Parameters	Reflection Mode
X-Ray wavelength	Cu, ka Kal (Â): l.540598, Ka2 (Â): 1.544426,
X-Ray tube setting	Ka2/Kal intensity ratio: 0.50 45 kV, 40 mA
Divergence slit	Fixed 1/8°
Scan mode	Continuous
Scan range	3-40
(° 2TH)
Scan step time [s]	18.87
Step size	0.0131
(° 2TH)
Test Time	____________4 min 15 s__________

Table 60: XRPD Peaks for Compound 33 2-MeTHF solvaté Form A

Peak #	Angle (Degrees 2-Thêta ±0.2)	Relative Intensity %
1	14.6	100.0__
2	18.6	86.7 _
3	14.5	73.2
4	7.0	49.7
5	7.0	46.4 _
6	21.0	40.2
7	20.9	38.4
8	18.8	36.2
9	17.3	26.5
10	22.2	22.2
11	20.2	21.4
12	20.4	17.4
13	31.7	16.8
14	9.9	16.0
15	28.6	15.6
16	16.3	15.2
17	23.1	15.1
18	19.7	13.4
19	8.8	13.2
20	22.7	13.0
21	27.1	12.8
22	13.7	12.6
23	17.9	12.5
24	17.6	12.2
25	23.6	10.4

583

Peak #	Angle (Degrees 2-Theta ±0.2)	Relative Intensîty %
26	__________________21.9______________	10.4

C. Thermogravimetrlc Analysis

Thermal gravimétrie analysis of Compound 33 Form L was measured using TA Discovery 550 TGA from TA Instrument. A sample with weight of approximately l-5 mg was scanned from 25 °C to around 290 °C at a heating rate of 10 °C/min with nitrogen purge. Data were collected by Thermal Advantage Q Sériés™ software and analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The TGA thermogram as provided in FIG. 17B shows 7.8 % weight loss from ambient température up to 200°C.

D. Differential Scanning Calorimetry Analysis

DSC of Compound 33 Form L was measured using the TA Q2000 DSC from TA Instrument. A sample with a weight between 1-10 mg was weighed into an aluminum pan. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed and a flow of nitrogen was passed through the cell. The heating program was set to heat the sample at a heating rate of 10° C/min around 270° C. When the run was completed, the data were analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The DSC thermogram as provided in FIG. 17C shows an endothermie peak around 159 JC.

18. Compound 33 Form M

A. Synthetic Procedure

About 15 mg of Compound 33 Form M was weighed into a 4 mL vial, which was placed into a 20 mL vial with 2 mL of MTBE. The 20 mL vial was sealed with a cap and kept at RT for ten days allowing solvent vapor to interact with the solid sample.

B. X-Ray Powder Diffraction

XRPD was performed with a Panaiytical X’Pert³ Powder XRPD on a Si zero-background holder. The 20 position was calibrated against a Panalytical Si reference standard dise. The parameters used are listed in the Table 61. The XRPD diffractogram is shown in FIG. 18A and XRPD data are summarized in Table 62.

Table 61: Parameters for XRPD test of Compound 33 Form M

584

Parameters	Reflection Mode
	Cu, ko
X-Ray wavelength	Καί (Â): 1.540598, Ka2 (Â): 1.544426
	Κα2/Κα1 intensity ratio: 0.50
X-Ray tube setting	45 kV, 40 mA
Divergence slit	Fixed 1/8°
Scan mode	Continuous
Scan range	3-40
(° 2TH)
Scan step time [s]	18.87
Step size	0.0131
(° 2TH)
Test Time	4 min 15 s

Table 62: XRPD Peaks for Compound 33 Form M

Peak #	Angle (Degrees 2-Theta ±0.2)	Intensity %
1	18.3	100.0
2	18.9	35.4
3	21.2	30.0
4	8.4	15.9
5	11.3	15.4
6	20.6	15.2
7	21.7	15.1
8	16.0	14.9
9	7.0	14.8
10	17.2	12.8
11	9.4	11.4
12	___________________13.8_______________	10.1

C. Thermogravimetric Analysis

TGA data was collected using a TA Discovery 550 TGA from TA Instrument. TGA was calibrated using nickel reference standard. Detaîled parameters used are listed in Table 63. The TSC thermogram as provided in FIG. 18B shows -15% weight loss from ambient température up to ~200°C.

Table 63: Parameters used for TGA and DSC analyses

Parameters TGA DSC

Method Ramp Ramp

Sample pan Platinum, open Aluminum, crimped

T emperature

Heating rate

RT - 300 °C

10°C/min

585

Purge gas N₂

D. Differential Scanning Calorimetry Analysis

DSC was performed using a TA Q2000 DSC from TA Instrument. DSC was calibrated with Indium reference standard. Detailed parameters used are listed in Table 63. The 5 thermogram as provided in FIG. 18C shows an endothermie peak at ~115 JC.

19. Compound 33 Form N

A. Synthetic Procedure

About 15 mg of Compound 33 Form A was suspended in 0.3 mL of EtOAc in a glass vial. After the suspension was stirred magnetically at room température, the remaining solids 10 were isolated.

B. X-Ray Powder Diffraction

XRPD was performed with a Panalytical X’Pert³ Powder XRPD on a Si zero-background holder. The 2Θ position was calibrated against a Panalytical Si reference standard dise. The parameters used are listed in the Table 64. The XRPD diffractogram is shown in FIG. 19A and 15 XRPD data are summarized in Table 65.

Table 64: Parameters for XRPD test of Compound 33 Form N

Parameters Reflection Mode

	Cu, ka
X-Ray wavelength	Kal (Â): 1.540598, Ka2 (Â): 1.544426
	Ka2/Kal intensity ratio: 0.50
X-Ray tube setting	45 kV, 40 mA
Divergence slit	Fixed 1/8°
Scan mode	Continuous
Scan range	3-40
(° 2TH)
Scan step time [s]	18.87
Step size	0.0131
(° 2TH)
Test Time	4 min 15 s

Table 65: XRPD Peaks for Compound 33 Form N

Peak #	Angle (Degrees 2-Theta ±0.2)	Intensity %
1	19.6	100.0
2	20.5	71.2

586

Peak #	Angle (Degrees 2-Theta±0.2)	Intensity %
3	18.7	69.6____
4	15.6	66.0
5	18.2	63.6__
6	21.8	43.0
7	23.1	39.0 ______
8	25.6	36.4
9	21.5	34.9
10	11.7	33.0
11	14.3	31.3__
12	24.0	28.8
13	26.1	25.3
14	12.3	24.7
15	13.0	23.9
16	19.2	21.7
17	17.6	19.9
! 18	17.1	18.0
19	22.2	15.0
20	8.8	14.6
21	26.8	14.3
22	4.2	13.9
23	22.7	13.7
24	28.4	12.5
25	12.6	11.1
26	28.0	10.4

C. Thermogravimetric Analysis

TGA data was collected using a TA Discovery 550 TGA from TA Instrument. TGA was calibrated using nickel reference standard. Detailed parameters used are listed in Table 66. The 5 TGA thermogram as provided in FIG. 19B shows -9% weight loss from ambient température up to —217 °C.

Table 66: Parameters used for TGA and DSC analyses

Parameters	TGA	DSC
Method	Ramp	Ramp
Sample pan	Platinum, open	Aluminum, crimped
Température		RT-3 00 C
Heatîng rate		10°C/min
Purge gas		N?

587

D. Differential Scanning Calorimetry Analysis

DSC was perfonned using a TA Q2000 DSC from TA Instrument. DSC was calibrated with Indium reference standard. Detailed parameters used are listed in Table 66. The DSC thermogram provided in FIG. 19C shows endothermie peaks at —477, 345L1C.

20. Compound 33 Form O

A. Synthetic Procedure:

About -20 mg of Compound 33 THF solvaté Form A was suspended in 0.1-0.3 mL of EtOAc in a 2 mL glass vial. After the suspension was stirred magnetically for two days at room temperature (RT), the remaîning solids were isolated.

B. X-Ray Powder Diffraction

XRPD was perfonned with a Panalytical X’Per? Powder XRPD on a Si zero-background holder. The 2Θ position was calibrated against a Panalytical Si reference standard dise. The parameters used are listed in the Table 67. The XRPD diffractogram is shown in FIG. 20A and XRPD data are summarized in Table 68.

Table 67: Parameters for XRPD test of Compound 33 Form O

Parameters Reflection Mode

Cu, ka

X-Ray wavelength	Καί (Â): 1.540598, Ka2 (Â): 1.544426 Κα2/Κα1 intensity ratio: 0.50
X-Ray tube setting	45 kV, 40 mA
Divergence sût	Fixed 1/8°
Scan mode	Continuons
Scan range (° 2TH)	3-40
Scan step time [s]	18.87
Step size (° 2TH)	0.0131
Test Time	4 min 15 s

Table 68: XRPD Peaks for Compound 33 Form O

Peak #	Angle (Degrees 2-Theta ±0.2)	Intensity %
1	7.0	100.0
2	21.2	70.6
3	17.4	64.5
4	10.4	41.3
5	19.5	38.5

588

Peak #	Angle (Degrees 2-Theta ±0.2)	Intensity %
6	18.8	31.8
7	16.9	31.3
8	22.9	28.2
9	20.4	28.1
10	21.6	22.3
11	23.3	19.6
12	8.8	16.0
13	16.6	14.6
14	22.3	13.7
15	15.5	13.1
16	______________________8.3_________________	11.5

C. Thermogravimetric Analysis

TGA data was collected using a TA Discovery 550 TGA from TA Instrument. TGA was calibrated using nickel reference standard. Detailed parameters used are listed in Table 69. The TGA thermogram as provided in FIG. 20B shows ~7% weight loss from ambient température up to ~200°C.

Table 69: Parameters used for TGA and DSC analyses

Parameters	TGA	DSC
Method	Ramp	Ramp
Sample pan	Platinum, open	Aluminum, crimpcd
Température		RT - 300 °C
Heating rate		10 °C/mîn
Purge gas		n2

21. Compound 33 Potassium Sait Form A

A. Synthetic Procedure

401 mg Compound 33 Form A was dissolved into 60 mL acetone at 50°C to get clear solution. And 74 mg KOFI was dissolved into 3 mL water for KOH aqueous solution. 3 mL Compound 33 acetone solution was dispensed in a glass vial at room température and 0.1 mL KOH aqueous solution was added into it. Compound 33 K sait A was obtained via évaporation at room température.

B. X-Ray Powder Diffraction

XRPD was performed with a Panalytical X’Pert³ Powder XRPD on a Si zero-background holder. The 20 position was calibrated against a Panalytical Si reference standard dise. The parameters used are listed in the Table 70. The XRPD diffractogram is shown in FIG. 21A and XRPD data are summarized in Table 71.

589

Table 70: Parameters for XRPD test of Compound 33 K sait Form A

Parameters	Reflection Mode
	Cu, ka
X-Ray wavelength	Kal (Â): 1.540598, Ka2 (Â): 1.544426
	Ka2/Kal intensity ratio: 0.50
X-Ray tube setting	45 kV, 40 mA
Divergence slit	Fixed 1/8°
Scan mode	Continuous
Scan range	3-40
(° 2TH)
Scan step time [s]	18.87
Step size	0.0131
(° 2TH)
Test Time	4 min 15 s

Table 71: XRPD Peaks for Compound 33 K Sait Form A

Peak #	Angle (Degrees 2-Theta ±0.2)	Intensity %
1	20.7	100.0
2	11.7	85.9
3	18.0	53.9

C. Thermogravimetric Analysis

TGA data was collected using a TA Discovery 550 TGA from TA Instrument. TGA was calibrated using nickel reference standard. Detaîled parameters used are listed in Table 72. The TGA thermogram provided in FIG. 21B shows -16% weight loss from ambient température up to~190°C.

D. Differential Scanning Caiorimetry Analysis

DSC was performed using a TA Q2000 DSC from TA Instrument. DSC was calibrated with Indium reference standard. Detaîled parameters used are listed in Table 72. The DSC thermogram provided in FIG. 21C shows endothermie peaks at~140 and 342°C.

22. Compound 33 Potassium Sait Form B

A. Synthetic Procedure

399 mg Compound 33 Form A was dissolved into 10 mL 1,4-dioxane ai 50°C with sonication to get clear solution. And 74 mg KOH was dissolved into 3 mL water for KOH aqueous solution. 0.5 mL Compound 1,4-dioxane solution was dispensed in a glass vial at room

590 température and O.l mL KOH aqueous solution was added into it. Compound 33 K sait B was isolated at room température.

B. X-Ray Powder Diffraction

XRPD was performed with a Panalytical X’Pert³ Powder XRPD on a Si zero-background holder. The 2Θ position was calibrated against a Panalytical Si reference standard dise. The parameters used are listed in the Table 73. The XRPD diffractogram is shown in FIG. 22A and XRPD data are summarized in Table 74.

Table 73: Parameters for XRPD test of Compound 33 K sait Form B

Parameters	Reflection Mode
	Cu, ka
X-Ray wavelength	Καί (Â): 1.540598, Ka2 (Â): 1.544426
	Κα2/Κα1 intensity ratio: 0.50
X-Ray tube setting	45 kV, 40 mA
Divergence slit	Fixed 1/8°
Scan mode	Continuous
Scan range	3-40
(° 2TH)
Scan step time [s]	18.87
Step size	0.0131
(° 2TH)
Test Time	4 min 15 s

Table 74: XRPD Peaks for Compound 33 K Sait Form B

Peak #	Angle (Degrees 2-Theta ±0.2)	Intensity %
1	10.8	100.0
2	21.7	74.8
3	17.5	58.1
4	9.1	40.4
5	6.9	34.6
6	15.3	33.2
7	20.0	32.3
S	20.6	21.0
9	____________________13 7________________	18.0

C. Thermogravimetric Analysis

TGA data was collected using a TA Discovery 550 TGA from TA Instrument. TGA was calibrated using nickel reference standard. Detailed parameters used are listed in Table 75. The

591

TGA thennogram provided in FIG, 22B shows -12% weight loss from ambient température up to~170°C.

Table 75: Parameters used for TGA and DSC analyses

Parameters	TGA	DSC
Method	Ramp	Ramp
Sample pan	Platinum, open	Aluminum, crimped
T emperature		RT-300 °C
Heating rate		10°C/min
Purge gas		n2

D. Differential Scanning Calorimetry Analysis

DSC was performed using a TA Q2000 DSC from TA Instrument. DSC was calibrated with Indium reference standard. Detailed parameters used are listed in Table 75. The DSC thennogram provided in FIG. 22C shows endothermie peaks at -98, 146 and 342 °C.

23. Compound 33 Potassium Sait Form C

A. Synthetic Procedure

402 mg Compound 33 Fonn A was dissolved into 60 mL acetone/water (v/v, 9: l) at 50°C to get clear solution. And 74 mg KOH was dissolved into 3 mL water for KO H aqueous solution. 3 mL Compound 33 acetone/water solution was dîspensed in a glass vial at room température and 0.1 mL KOH aqueous solution was added into it. Compound 33 K sait C was obtained via évaporation at room température.

B. X-Ray Powder Diffraction

XRPD was performed with a Panalytical X’Pert³ Powder XRPD on a Si zero-background holder. The 2Θ position was calibrated against a Panalytical Si reference standard dise. The parameters used are listed in the Table 76. The XRPD diffractogram is shown in FIG. 23A and XRPD data are summarized în Table 77.

Table 76: Parameters for XRPD test of Compound 33 K sait Form C

592

Parameters Reflection Mode

	Cu, ka
X-Ray wavelength	Καί (Â): 1.540598, Ka2 (Â): 1.544426
	Κα2/Κα1 intensity ratio: 0.50
X-Ray tube setting	45 kV, 40 mA
Divergence slit	Fixed 1/8°
Scan mode	Continuous
Scan range	3-40
(° 2TH)
Scan step time [s]	18.87
Step size	0.0131
(° 2TH)
Test Time	4 min 15 s

Table 77: XRPD Peaks for Compound 33 K Sait Form C

Peak #	Angle (Degrees 2-Theta ±0.2)	Intensity % _
1	16.8	100.0
2	6.7	77.7
3	19.3	74.1
4	____________________10.5_______________	46.2

C. Thermogravimetric Analysis

TGA data was collected using a TA Discovery 550 TGA from TA Instrument. TGA was calibrated using nickel reference standard. Detailed parameters used are listed in Table 78. The TGA thermogram provided in FIG. 23B shows -17% weight loss from ambient température up to~190°C.

Table 78: Parameters used for TGA and DSC analyses

Parameters	TGA	DSC
Method	Ramp	Ramp
Sample pan	Platinum, open	Aluminum, crimped
Température		RT - 300 °C
Heating rate		10°C/min
Purge gas		n2

593

D. Differential Scanning Calorimetry Analysis

DSC was perfonned using a TA Q2000 DSC from TA Instrument. DSC was calibrated with Indium reference standard. Detailed parameters used are listed in Table 78. The DSC thennogram provided in FIG. 23C shows endothennic peaks at —110, 145 and 328 °C.

Example 4: Spray Dried Dispersions (SDD) of Amorphous Forms of Compound 33

Various spray dried dispersions (SDD) of amorphous fonns of Compound 33 were prepared using either 50% or 80% drug loading (DL) and with different polymers (e.g., HPMCAS-H, PVPVA, HPMC El 5), different organic solvent Systems (e.g., DCM, EtOH, THF, Me-THF) and at different amounts of water.

X-ray powder diffraction (XRPD) spectra were recorded at room température in transmission mode using a PANalytical Empyrean system equipped with a sealed tube source and a PIXcel ID Medîpix-3 detector (Malvern PANalytical Inc, Westborough, Massachusetts). The X-Ray generator operated at a voltage of 45 kV and a current of 40 mA with copper radiation (1.54060 Â). The powder sample was placed on a 96 well sample holder with mylar film and loaded into the instrument. The sample was scanned over the range of about 3° to about 40°2θ with a step size of 0.0131303° and 49s per step.

For ssNMN analysis, Bruker-Biospin 400 MHz wide-bore spectrometer equipped with Bruker-Biospin 4mm HFX probe was used. Samples were packed into 4mm ZrCb rotors and spun under Magic Angle Spinning (MAS) condition with spinning speed typically set to 12.5 kHz. The proton relaxation time was measured using 'H MAS T। saturation recovery relaxation experîment in order to set up proper recycle delay of the ^l3C cross-polarization (CP) MAS experîment. The fluorine relaxation time was measured using ^l9F MAS Ti saturation recovery relaxation experîment in order to set up proper recycle delay of the ^l9F MAS experîment. The CP contact time of carbon CPMAS experîment was set to 2 ms. A CP proton puise with linear ramp (from 50% to 100%) was employed. The carbon Hartmann-Hahn match was optimized on extemal reference sample (glycine). Both carbon and fluorine spectra were recorded with proton decoupiing using TPPM15 decoupling sequence with the field strength of approximately 100 kHz.

1. Compound 33 50%DL Amorphous Spray Dried Dispersion

[DCM/EtOH/10% Water with HPMCAS-H] (Composition used in clinical suspension in Phase I)

A. Synthetic Procedure

125 g of Compound 33 was weighed into a bottle. 2875 g of 56.8/33.7/9.5 DCM/EtOH/Water was added. The bottle was capped and the contents were stirred for -1 h at 594 ambient température when a clear solution resulted. 125 g of hydroxypropylmethylcellulose acetate succinate H grade (HPMCAS-H) was added. The bottle was capped and the contents were stirred for ~2hrs at ambient température when a clear solution resulted. This solution was then spray dried to make amorphous Compound 33.

B. X-Ray Powder Diffraction

X-ray powder diffraction (XRPD) spectra were recorded at room température in transmission mode using a PANalytical Empyrean system. The XRPD diffractogram is shown in FIG. 24A.

B. Differential Scanning Calorimetry

Modulated Differential Scanning Calorimetry Analysis of Compound 33 amorphous form was carried out using the TA Instruments Discovery DSC. The thermogram as provided in FIG. 24B shows a glass transition at ~14O°C_Ï a recrystallization at ~175°C and a melt endotherm at ~2l5°C.

C. Thermal Gravimétrie Analysis

Thermal Gravimétrie Analysis of Compound 33 amorphous form was carried out using the TA Instruments Discovery TGA. The thermogram as provided in FIG. 24C shows a weight loss of-0.37.

2. 50%DL Amorphous Spray Dried Dispersion [DCM/EtOH/10%Water with PVPVA]

A. Synthetic Procedure g of Compound 33 was weighed into a bottle. 23 g of 56.8/33.7/9.5 DCM/EtOH/Water was added. The bottle was capped and the contents were stirred for ~1 h at ambient température when a clear solution resulted. 1 g of polyvinylpyrrolidone/vînyi acetate PVPVA was added. The bottle was capped and the contents were stirred for ~2 h at ambient température when a clear solution resulted. This solution was then spray dried to make amorphous Compound 33.

B, X-Ray Powder Diffraction

X-ray powder diffraction (XRPD) spectra were recorded at room température in transmission mode using a PANalytical Empyrean system. The XRPD diffractogram is shown in FIG. 25A.

C. Differential Scanning Calorimetry

Modulated Differential Scanning Calorimetry Analysis of Compound 33 amorphous form was carried out using the TA Instruments Discovery DSC. The thermogram as provided in FIG. 25B shows a glass transition at -153°C.

3. Compound 33 50%DL Amorphous Spray Dried Dispersion

[DCM/EtOH/10%Water with HPMC E15|

A. Synthetic Procedure

595 l g of Compound 33 was weighed into a bottle. 23 g of 56.8/33.7/9.5 DCM/EtOH/Water was added. The bottle was capped and the contents were stirred for -1 h at ambient température when a clear solution resulted. 1 g of hydroxypropylmethylcellulose (HPMC) El5 was added. The bottle was capped and the contents were stirred for -2 h ai ambient température when a clear solution resulted. This solution was then spray dried to make amorphous Compound 33.

B. X-Ray Powder Diffraction

X-ray powder diffraction (XRPD) spectra were recorded at room température in transmission mode using a PANalytical Empyrean system. The XRPD diffractogram is shown in FIG. 26A.

C. Differential Scanning Calorimetry

Modulâted Differential Scanning Calorimetry Analysis of Compound 33 amorphous form was carried out using the TA Instruments Discovery DSC. The thermogram as provided in FIG. 26B shows a glass transition at ~155°C.

4. Compound 33 50%DL Amorphous Spray Dried Dispersion [DCM/EtOH/l%Water with HPMCAS-H]

A. Synthetic Procedure

125 g of Compound 33 was weighed into a bottle. 4750 g of 70/29/1 DCM/EtOH/Water was added. The bottle was capped and the contents were stirred for ~1 h at ambient température when a clear solution resulted. 125 g of HPMCAS-H was added. The bottle was capped and the contents were stirred for ~2 h at ambient température when a clear solution resulted. This solution was then spray dried to make amorphous Compound 33.

B. X-Ray Powder Diffraction

X-ray powder diffraction (XRPD) spectra were recorded at room température in transmission mode using a PANalytical Empyrean system. The XRPD diffractogram is shown in FIG. 27A.

C. Differential Scanning Calorimetry

Moduiated Differential Scanning Calorimetry Analysis of Compound 33 amorphous form was carried out using the TA Instruments Discovery DSC. The thermogram as provided in FIG. 27B shows a glass transition at -145°C and a recrystallization at ~195°C.

D, Thermal Gravimétrie Analysis

Thermal Gravimétrie Analysis of Compound 33 amorphous fonn was carried out using the TA Instruments Discovery TGA. The thermogram as provided in FIG. 27C shows a weight loss of-0.53.

5. Compound 33 50%DL Amorphous Spray Dried Dispersion [DCM/EtOH/l%Water with HPMCAS-H]

596

A. Synthetic Procedure

360 g of Compound 33 was weighed into a bottle. 11.288 g of 65.98/27.17/0.87 DCM/EtOH/Water was added. The bottle was capped and the contents were stirred for -l h at ambient temperature when a clear solution resulted. 360 g of HPMCAS-H was added. The bottle was capped and the contents were stirred for ~2 h at ambient temperature when a clear solution resulted. This solution was then spray dried to make amorphous Compound 33.

B. X-Ray Powder Diffraction

X-ray powder diffraction (XRPD) spectra were recorded at room temperature in transmission mode using a PANalytical Empyrean system (ELN 190524-009). The XRPD diffractogram is shown în FIG. 28A.

C. Differential Scanning Calorimetry

Modulated Differential Scanning Calorimetry Analysis of Compound 33 amorphous fonn was canied out using the TA Instruments Discovery DSC. The thermogram as provided in FIG. 28B shows a glass transition at -145°C, a recrystallization at ~200°C and a melt endothenn at -275°C.

D. Thermal Gravimétrie Analysis

Thermal Gravimétrie Analysis of Compound 33 amorphous form was carried out using the TA Instruments Discovery TGA. The thermogram as provided in FIG. 28C shows a weight loss of-0.40.

6. Compound 33 50%DL Amorphous Spray Dried Dispersion [DCM/EtOH/1% Water with HPMCAS-H])

A. Synthetic Procedure g of Compound 33 was weighed into a bottle. 1450 mL of 59/40/1 DCM/EtOH/Water was added. The bottle was capped and the contents were stirred for -1 h at ambient temperature when a clear solution resulted. 47 g of HPMCAS-H was added. The bottle was capped and the contents were stirred for -2 h at ambient temperature when a clear solution resulted. This solution was then spray dried to make amorphous Compound 33.

B. X-Ray Powder Diffraction

X-ray powder diffraction (XRPD) spectra were recorded at room temperature in transmission mode using a PANalytical Empyrean system. The XRPD diffractogram is shown in FIG. 29A.

C. Differential Scanning Calorimetry

Modulated Differential Scanning Calorimetry Analysis of Compound 33 amorphous form was carried out using the TA Instruments Discovery DSC. The thermogram as provided in FIG. 29B shows a glass transition at ~144°C and a recrystallization at -213°C.

597

7. Compound 33 50%DL Amorphous Spray Dried Dispersion [THF/Water with HPMCAS-H]

A. Synthetic Procedure g of 50%DL Compound 33 (with HPMCAS-H) was weighed into a bottle. 144 g of 90/10 THF/Water was added. The bottle was capped and the contents were stirred for -2 h at ambient température when a clear solution resulted. This solution was then spray dried to make amorphous Compound 33.

B. X-Ray Powder Diffraction

X-ray powder diffraction (XRPD) spectra were recorded at room température in transmission mode using a PANalytical Empyrean system. The XRPD diffractogram is shown in FIG. 30A.

C. Differential Scanning Calorimetry

Modulated Differential Scanning Calorimetry Analysis of Compound 33 amorphous form was carried oui using the TA Instruments Discovery DSC. The thermogram as provided in FIG. 30B shows a glass transition at ~140°C and a recrystallization at ~195°C.

D. Thermal Gravimétrie Analysis

Thermal Gravimétrie Analysis of Compound 33 amorphous form was carried out using the TA Instruments Discovery TGA. The thermogram as provided in FIG. 30C shows a weight loss of-0.40.

E. Solid State NMR Analysis ^l3C ssNMR data for a spray dried dispersion of 50%DL Compound 33 with HP MC AS from THF is provided in FIG. 30D and summarized in Table 79A below.

Table 79A: 13C ssNMR for SDD of 50% Compound 33/HPCMAS

Peak #	Chem Shift [ppm]	Intensity [rel]
l	173.1	11.4
2	170.0	22.2
3	167.2	12.6
4	163.9	___9.8
5	161.5	15.1
6	144.4	13.1
7	141.2	18.3
8	137.8	39.3
9	130.9	100.0
10	121.7	26.6
11	116.5	34.9
12	103.0	25.7
13	98.4	30.6
14	83.5	35.2
15	74.1	__________65.1

59S

Peak #	Chem Shift [ppm]	Intensîty [rel}_
16	68.5	58.2
17	60.5	53.4
18	35.8	39.2
19	30.7	23.3
20	20.6	30.8
21	16.5	9.6

^,9F ssNMR data for a spray dried dispersion of 50%DL Compound 33 with HPMCASÊOm THF is provided in FIG. 30E and summarized in Table 79B.

Peak #	Chem Shift [ppm]	Intensîty [rel]
1	-112.6	12.5

8. Compound 33 50%DL Amorplious Spray Dried Dispersion [2-MeTHF/EtOH/Water with HPMCAS-H]

A. Synthetic Procedure g of Compound 33 was weighed into a bottle. 108 g of 80/13/7 2-MeTHF/EtOH/Water was added. The bottle was capped and the contents were stirred for ~1 h at ambient température when a clear solution resulted. 6 g of HPMCAS-H was added. The bottle was cappcd and the contents were stirred for -2 h at ambient température when a clear solution resulted. This solution was then spray dried to make amorphous Compound 33.

B. X-Ray Powder Diffraction

X-ray powder diffraction (XRPD) spectra were recorded at room température in transmission mode using a PANalytical Empyrean system The XRPD diffractogram is shown in FIG. 3IA

C. Differential Scanning Calorimetry

Modulated Differential Scanning Calorimetry Analysis of Compound 33 amorphous form was carried out using the TA Instruments Discovery DSC. The thermogram as provided in FIG. 31B shows a glass transition at ~145°C and a recrystallization at ~180°C.

D. Thermal Gravimétrie Analysis

Thermal Gravimétrie Analysis of Compound 33 amorphous form was carried out using the TA Instruments Discovery TGA. The thermogram as provided in FIG. 31C shows a weight loss of~0.65.

599

9. Compound 33 80%DL Amorphous Spray Dried Dispersion [DCM/EtOH/Water with HPMCAS-H]

A. Synthetic Procedure

160 g of Compound 33 was weighed into a bottle. 3800 g of 56.8/33.7/9.5 DCM/EtOH/Water was added. The bottle was capped and the contents were stirred for ~l h at ambient température when a clear solution resulted. 40 g of HPMCAS-H was added. The bottle was capped and the contents were stirred for -2 h at ambient température when a clear solution resulted. This solution was then spray dried to make amorphous Compound 33.

B. X-Ray Powder Diffraction

X-ray powder diffraction (XRPD) spectra were recorded at room température in transmission mode using a PANalytîcal Empyrean system. The XRPD diffractogram is shown in FIG. 32A

C. Differential Scanning Calorimetry

Moduiated Differential Scanning Calorimetry Analysis of Compound 33 amorphous form was carried out using the TA Instruments Discovery DSC. The thermogram as provided in FIG. 32B shows a glass transition at ~!64°C and a recrystallization at ~l80°C.

D. Thermal Gravimétrie Analysis

Thermal Gravimétrie Analysis of Compound 33 amorphous form was carried out using the TA Instruments Discovery TGA. The thermogram as provided in FIG. 32C shows a weight loss of-0.02.

11. Compound 33 80%DL Amorphous Spray Dried Dispersion [DCM/EtOH/Water with HPMCAS-H, starting with THF Solvaté DS]

A. Synthetic Procedure

7.9 g of Compound 33 THF Solvaté was weighed into a bottle. 500 g of 56.8/33.7/9.5 DCM/EtOH/Water was added. The bottle was capped and the contents were stirred for ~1 h at ambient température when a clear solution resulted. 2.0 g of HPMCAS-H was added. The bottle was capped and the contents were stirred for ~2 h at ambient température when a clear solution resulted. This solution was then spray dried to make amorphous Compound 33.

B. X-Ray Powder Diffraction

X-ray powder diffraction (XRPD) spectra were recorded at room température in transmission mode using a PANalytîcal Empyrean system. The XRPD diffractogram is shown in FIG. 33A

C. Differential Scanning Calorimetry

600

Modulated Differential Scanning Calorimetry Analysis of Compound 33 amorphous fonn was carried out using the TA Instruments Discovery DSC. The thermogram provided in FIG. 33B shows a giass transition at ~165°C.

11. Compound 33 80%DL Amorphous Spray Dried Dispersion [THF/Water with

HPMCAS-H]

A. Synthetic Procedure

200 g of Compound 33 was weighed into a bottle. 2875 g of 90/10 THF/Water was added. The bottle was capped and the contents were stirred for -1 h at ambient température when a clear solution resulted. 50 g of HPMCAS-H was added. The bottle was capped and the contents were stirred for ~2 h at ambient température when a clear solution resulted. This solution was then spray dried to make amorphous Compound 33.

B. X-Ray Powder Diffraction

X-ray powder diffraction (XRPD) spectra were recorded at room température in transmission mode using a PANalytical Empyrean system. The XRPD diffractogram is shown in

FIG. 34A.

C. Differential Scanning Calorimetry

Modulated Differential Scanning Calorimetry Analysis of Compound 33 amorphous form was carried out using the TA Instruments Discovery DSC. The thermogram as provided in FIG. 34B shows a giass transition at ~I67°C.

D. Solid State NMR Analysis ¹³ C ssNMR data for a spray dried dispersion of 80% Compound 33 with HPMCAS-from THF is provided in FIG. 34C and summarized in Table 80A below.

Table 80A: ^,3C ssNMR for SDD of 80% Compound 33/HPCMAS

Peak #	Chem Shift [ppm]	Intensity [rel]
1	173.0	5.7
2	169.6	11.1
3	163.8	8.7
4	161.2	12.7
5	144.1	13.6
6	140.9	18.3
7	137.6	37.9
8	130.9	100.0
9	121.6	24.2
10	116.3	35.0
11	103.2	8.1
12	98.1	25.1
13	82.9	9.4
14	74.6	17.6
15	68.2_______	44.3

601

Peak #	Chem Shift [ppm]	Intensity [rel]
16	60.5	13.4
17	35.6	38.6
18	31.5	20.0
19	_____________20.1_________	8.3

^WF ssNMR data for a spray dried dispersion of 80%DL Compound 33 with HPMCASfrom THF is provided in FIG. 34D and summarized in Table 80B.

Table 80B: ¹⁹F ssNMR for SDD of 80% Compound 33/HPCMAS

Peak #	Chem Shift [ppm]	Intensity [rel]
1	-112.6	___12.5

12. Compound 33 80%DL Amorphous Spray Dried Dispersion [THF/Water with PVPVA]

A. Synthetic Procedure

1.6 g of Compound 33 was weighed into a bottle. 18 g of 90/10 THF/Water was added.

The bottle was capped and the contents were stirred for -1 h at ambient température when a clear solution resulted. 0.4 g of PVPVA was added. The bottle was capped and the contents were stirred for ~2 h at ambient température when a clear solution resulted. This solution was then spray dried to make amorphous Compound 33.

B. X-Ray Powder Diffraction

X-ray powder diffraction (XRPD) spectra were recorded at room température in transmission mode using a PANalytical Empyrean system. The XRPD diffractogram is shown in FIG. 35A.

C. Differential Scanning Calorimetry

Modulated Differential Scanning Calorimetry Analysis of Compound 33 amorphous form 20 was carried out using the TA Instruments Discovery DSC. The thermogram provided in FIG.

35B shows a glass transition at -177°C, a recrystallization at ~205°C and a melt endotherm at ~230°C.

13. Compound 33 80%DL Amorphous Spray Dried Dispersion [THF/Water with HPMC E15]

A. Synthetic Procedure

1.6 g of Compound 33 was weighed into a bottle. 18 g of 90/10 THF/Water was added. The bottle was capped and the contents were stirred for -1 h at ambient température when a clear solution resulted. 0.4 g of HPMC E15 was added. The bottle was capped and the contents were stirred for -2 h at ambient température when a clear solution resulted. This solution was then spray dried to make amorphous Compound 33.

602

B. X-Ray Powder Diffraction

X-ray powder diffraction (XRPD) spectra were recorded at room température in transmission mode using a PANalytical Empyrean system. The XRPD diffractogram is shown m FIG. 36A.

C. Differential Scanning Calorimetry

Modulated Differential Scanning Calorimetry Analysis of Compound 33 amorphous form was carried out using the TA Instruments Discovery DSC. The thermogram as provided in FIG. 36B shows a glass transition at ~172°C, a recrystallization at ~2lO°C and a melt endotherm at -320°C.

14. Compound 33 80%DL Amorphous Spray Dried Dispersion [2-MeTHF/EtOH/Water with HPMCAS-H]

A. Synthetic Procedure g of Compound 33 was weighed into a bottle. 180 g of 80/13/7 2MeTHF/EtOH/Water was added. The bottle was capped and the contents were stirred for -1 h at ambient température when a clear solution resulted. 4 g of HPMCAS-H was added. The bottle was capped and the contents were stirred for -2 h at ambient température when a clear solution resulted. This solution was then spray dried to make amorphous Compound 33.

B. X-Ray Powder Diffraction

X-ray powder diffraction (XRPD) spectra were recorded at room température in transmission mode using a PANalytical Empyrean system. The XRPD diffractogram is shown in FIG. 37A

C. Differential Scanning Calorimetry

Modulated Differential Scanning Calorimetry Analysis of Compound 33 amorphous form was carried out using the TA Instruments Discovery DSC. The thermogram in FIG. 37B shows a glass transition at ~169°C and a recrystallization at ~200°C.

D. Thermal Gravimétrie Analysis

Thermal Gravimétrie Analysis of Compound 33 amorphous form was carried out using the TA Instruments Discovery TGA. The thermogram of FIG. 37C shows a weight loss of -0.07.

15. Compound 33 Neat Amorphous Spray Dried Material [DCM/EtOH/Water without polymer]

A. Synthetic Procedure

3.5g of Compound 33 was weighed into a bottle. 100 mL of 60/39/1 DCM/EtOH/Water was added. The bottle was capped and the contents were stirred for approximateylhour at

603 ambient température to provide a clear solution. This solution was then spray dried to make neat amorphous Compound 33.

B. X-Ray Powder Diffraction:

X-ray powder diffraction (XRPD) spectra were recorded at room température in transmission mode using a PANalytîcal Empyrean system. The XRPD diffractogram is shown in FIG. 38A

C. Differential Scanning Calorimetry

Moduiated Differential Scanning Calorimetry Analysis of Compound 33 neat amorphous form was carried out using the TA Instruments Discovery DSC. The thermogram in FIG. 38B shows a glass transition at ~186°C.

D. SSNMR on Neat Amorphous Compound 33

Solid state ^l3C NMR data for neat amorphous Compound 33is provided in FIG. 38C and summarized in Table 79 below.

Table 81A: ^l3C ss NMR for Neat Amorphous Compound 33

Peak #	Chem Shift [ppm]	Intensity [rel]
l	172.5	4.9
2	170.1	8.2
3	167.0	7.6
4	163.7	8.4
5	161.6	11.3
6	144.5	12.4
7	140.8	17.7
8	137.4	35.3
9	130.7	100.0
10	121.4	22.8
H	115.7	35.8
12	97.6	23.0
13	67.9	42.9
14	35.5	39.3
15	31.5	20.0

Solid State ^l9F ssNMR data for neat amorphous Comopound 33 is provided in FIG. 38D and summarized in Table 80.

Table 81B: ¹⁹F ssNMR for Neat Amorphous Compound 33

Peak #	Chem Shift [ppm]	Intensity [rel]
1	-112.8	12.5

Other Embodiments

This disclosure provides merely exemplary embodiments of the invention. One skilled in the art will readily recognize from the disclosure and accompanying figures and claims, that 604 various changes, modifications and variations can be made therein without départing from the spirit and scope of the invention as defined in the following claim

Claims (52)

1. l. A compound of formula (1):

   a tautomer thereof, a pharmaceutically acceptable sait of any of the foregoing, and/or a deuterated derivatîve of any of the foregoing;

   wherein:

   (i) R° is chosen from (a) Ci-C₈ linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 R^A; and (b) 5- to 14-membered aromatic rings optionally substituted with 1 -4 R^A;

   wherein each R^A is independently chosen from halogens, cyano, hydroxy, thiol, sulfonic acid, sulfonamide, sulfinamide, amino, amide, carboxylic acid, 5- to 10-membered aromatic rings, and Ci-C^ linear, branched, and cyclic groups, wherein the amide nitrogen atom in the amide of R^A is optionally substituted with a heterocyclyl group that is optionally further substituted with oxo, wherein the Cs-Cô linear, branched, and cyclic groups are chosen from alkyl, alkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, alkylsulfonamide. alkylsulfmamide, aminoalkyl, and alkylamide, wherein the 5- to 10-membered aromatic rings and Cj-Cû linear, branched, and cyclic groups are optionally substituted with 1-4 substituents selected from halogens, Cj-Cô linear, branched, and cyclic groups and methoxy, and wherein an R^A group is optionally linked to an R^B group on an R² group;

   (ii) R¹ is chosen from (a) hydrogen.

   606 (b) Cj-Cg linear, branched, and cyclic alkyl groups. wherein the alkyl group is optionally substituted with l -4 substituents independently chosen from halogens, cyano, cyanoalkyl, hydroxy, alkylsulfonyl, and

   Cj-Côlinear, branched, and cyclic groups, wherein the Ci-Cè linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the Cj-C^ linear, branched, and cyclic groups are optionally substituted with l-4 substituents independently chosen from halogens, hydroxy, and

   Ci-Cf, linear, branched, and cycfic alkoxy groups, (c) Ci-C₈ linear, branched, and cyclic alkoxy or cyclic ihioalkyl groups optionally substituted with l-4 substituents independently chosen from halogens, cyano, cyanoalkyl;

   sulfone, sulfonamide, hydroxy, and Cj-Cô linear, branched, and cyclic alkyl groups that are optionally substituted with l-4 halogens or alkoxy groups (d) C|-Cô linear, branched, and cyclic alkylsulfonyl groups optionally substituted with Ci-C₆ linear or branched alkyl groups;

   (e) aminosulfonyl groups, optionally substituted with l or 2 substituents independently chosen from

   Ci-C₆ linear, branched, and cyclic alkyl groups;

   (f) Ci-C& linear, branched, and cyclic alkylsulfonyl amino groups; and (g) phosphine oxide groups, optionally substituted with 1 or 2 substituents independently chosen from

   C]-C& linear, branched, and cyclic alkyl groups;

   607 (h) Cj-Cô linear, branched, and cyclic trialkylsilyl groups;

   (i) Cj-Cô alkylamide;

   (iîi) R² is chosen from:

   (iv) X^l and X² are independently chosen from hydrogen, halogens, cyano, hydroxy, CiG linear, branched, and cyclic groups wherein the C|-Cô linear, branched, and cyclic groups are independently chosen from alkyl, alkoxy, thioalkyl, and aminoalkyl groups, and wherein the Ci~C₆ linear, branched, and cyclic groups are optionally substituted by l-4 independently chosen halogens;

   (v) each of W¹ and W² is independently selected from C and N;

   (vi) each---represents a single or double bond, provided that no more than one

   - is a double bond;

   (vii) each R³ is independently chosen from hydrogen, halogens, cyano, Ci-C₆ linear, branched, and cyclic alkyl groups, and Ci-C₆ linear, branched, and cyclic alkoxy groups, wherein the Ci-Cô linear, branched, and cyclic alkyl groups and the Ci-C₆ linear, branched, and cyclic alkoxy groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy groups, and carboxylic acid;

   (viii) n is an înteger chosen from 0, 1,2, and 3; and (ix) Z¹, Z², and Z³ are independently chosen from carbon, nitrogen, sulfur, and oxygen, wherein when Z¹, Z², and/or Z³ are carbon or nitrogen, the valences of carbon and nitrogen are completed with hydrogen atoms, halogen, Ci-Cô linear, branched, and cyclic alkyl groups, and Ci-Cô linear, branched, and cyclic alkoxy groups, wherein the Cj-Cô linear, branched, and cyclic alkyl groups and the Cj-Cô linear, branched, and cyclic alkoxy groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy groups, and carboxylic acid.

   608
2. 2. A compound of formula (I):

   a tautomer thereof, a pharmaceutically acceptable sait of any of the foregoing, and/or a deuterated derîvative of any of the foregoing;

   5 wherein:

   (i) R° is chosen from (a) Ci-Cg linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with l-4 R^A; and (b) 5- to 14-membered aromatic rings optionally substituted with l-4 R^A;

   j 0 wherein each R^A is independently chosen from halogens, cyano, hydroxy, thiol, sulfonic acid, sulfonamide, sulfmamide, amino, amide, carboxylic acid, 5- to lO-membered aromatic rings, and C|-C₆ linear, branched, and cyclic groups, wherein the amide nitrogen atom in the amide of R^A is optionally substituted with a heterocyclyl group that is optionally further substituted with oxo,

   15 . wherein the Ci-Cô linear, branched, and cyclic groups are chosen from alkyl, alkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, aïkylsulfonamide, alkylsulfïnamide, aminoalkyl, and alkylamide, wherein the 5- to 10-membered aromatic rings and Cj-Cô linear, branched, and cyclic groups are optionally substituted with 1-4 substituents

   20 selected from halogens, Ci-C₆ linear, branched. and cyclic groups and methoxy, and wherein an R^A group is optionally lînked to an R^B group on an R² group;

   (ii) R¹ is chosen from (a) hydrogen,

   25 (b) Cj-Cg linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 substituents independently chosen from halogens,

   609 cyano, cyanoalkyl.

   hydroxy, alkylsulfonyl, and

   Ci-CL linear, branched, and cyclic groups, wherein the Ci-C₆ linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the C|-C₆ linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy,and

   Ci-C₆ linear, branched, and cyclic alkoxy groups, (c) Cj-Cs linear, branched, and cyclic alkoxy or cyclic thioalkyl groups optionally substituted with 1-4 substituents independently chosen from halogens, cyano, cyanoalkyl;

   sulfone, sulfonamide, hydroxy, and C1-C& linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 halogens or alkoxy groups (d) Ci-Cô linear, branched, and cyclic alkylsulfonyl groups optionally substituted with Cj-C_& linear or branched alkyl groups;

   (e) aminosulfony] groups, optionally substituted with 1 or 2 substituents independently chosen from

   Cj-Cô linear, branched, and cyclic alkyl groups;

   (f) C|-Cê linear, branched, and cyclic alkylsulfonyl amino groups; and (g) phosphine oxide groups, optionally substituted with 1 or 2 substituents independently chosen from

   C|-C₆ linear, branched, and cyclic alkyl groups;

   (h) Ci-Cô linear, branched, and cyclic trialkyIsîlyl groups;

   (i) Ci-C₆ alkylamide;

   610 (iii) R² is chosen from 5- and 6-membered heterocyclîc rings (optionally substituted with oxo and/or C|-C₆ linear and branched alkyl groups) and 5- to 6-membered aromatic rings comprising 0-4 heteroatoms chosen from O, N. and S, wherein the 5-membered aromatic ring is optionally substituted with l-4 R^B groups and the 6-membered aromatic ring is optionally substituted with l -5 R^B groups, wherein the R^B groups are independently chosen from:

   amîdes, optionally substituted with l-3 groups selected from Ci-Cé linear, branched, and cyclic alkyl groups (optionally substituted with heteroaryl), 4- to 6membered heterocyclyl (optionally substituted with oxo, CrQ, linear, branched, and cyclic alkyl groups, hydroxyalkyl, amide, alkylsuifonyl, and acetamide); or wherein the amide nitrogen atom forms part of a 3- to 8-membered heterocyclyl ring (optionally substituted with alkylsuifonyl or C_rC₆ linear, branched, and cyclic alkyl group), imidazolidine-2,4-dione, heterocyclyls, optionally substituted with one more groups independently chosen from oxo, acyl, and C_rC₆ linear, branched, and cyclic alkyl group (which îs optionally further substituted with l-3 groups independently chosen from oxo, hydroxy, and acyl), phosphorous acid optionally esterified with a Cj-Cô linear, branched, or cyclic alkyl group, di(C|-C6)alkylphosphine oxides, (Ci-Côjalkylphosphinic acids optionally esterified with a Ci-C_& linear, branched, or cyclic alkyl group, halogens, cyano, hydroxy, carboxylic acids optionally esterified with a uronic acid or a Ci-C₆ linear, branched, or cyclic alkyl group, oxo, dihydroxylboryl,

   5- and 6-membered aromatic rings comprising 0-4 heteroatoms independently chosen from O, N, and S, optionally substituted with l or 2 substituents independently chosen from Ci-Cô linear, branched, and cyclic alkyl groups that are optionally substituted with 14 substituents independently chosen from

   611 hydroxy.

   carboxylîc acids, pyrrolidîn-2-one.

   C|-C₆ linear, branched, and cyclic alkyl groups. and

   C]-C₆ linear, branched, and cyclic alkylsulfonyl groups, and

   C_rC₆ linear, branched, and cyclic alkoxy groups, sulfonic acid, alkylsulfonamide,

   C_rC₆ linear, branched, and cyclic alkylsulfonyl groups, aminosulfonyl groups, optionally substituted with l or 2 substituents independently chosen from

   Ci-C₆ linear, branched, and cyclic alkyl groups,

   C]-C& linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, carboxylîc acid, Ci-C& linear, branched, and cyclic alkoxy groups, heterocyclyl optionally substituted with oxo, and amide,

   Ci-C₆ linear, branched, and cyclic alkoxy groups that are optionally substituted with 1 -4 substituents independently chosen from halogens, hydroxy, carboxylîc acid, Ci-Cè linear, branched, and cyclic alkyl groups, and

   Ci-C& linear, branched, and cyclic alkoxy groups, and tetrazolyl groups that are optionally substituted with substituents chosen from halogens, hydroxy, carboxylîc acid,

   C|-C₆ linear, branched, and cyclic alkyl groups, and

   C]-Cô linear, branched, and cyclic alkoxy groups,

   612 wherein 2 adjacent hydrogens on the 5- or 6-membered aromatic ring can be replaced by attachments to a second 5- or 6-membered aromatic ring comprising 0-4 heteroatoms independently chosen from O, N, and S to form a bicyclic R² group that is optionally substituted with l-6 R^B groups;

   (iv) X¹ and X² are independently chosen from hydrogen, halogens, cyano, hydroxy, CiCô linear, branched. and cyclic groups wherein the Cj-Cô linear, branched, and cyclic groups are independently chosen from alkyl, alkoxy, thioalkyl, and aminoalkyl groups, and wherein the Cj-Cô linear, branched, and cyclic groups are optionally substituted by 1-4 independently chosen halogens;

   (v) each of W¹ and W² îs independently selected from C and N;

   (vi) each - — represents a single or double bond, provided that no more than one

   ---is a double bond;

   (vii) each R³ is independently chosen from hydrogen, halogens, cyano, Cj-Cô linear, branched, and cyclic alkyl groups, and C|-Cô linear, branched, and cyclic alkoxy groups, wherein the Cj-Cô linear, branched, and cyclic alkyl groups and the Cj-Cô linear, branched, and cyclic alkoxy groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy groups, and carboxylic acid;

   (viii) n is an integer chosen from 0, 1,2, and 3; and (îx) two of Z¹, Z², and Z³ are nitrogen and the other is chosen from carbon and nitrogen, wherein the valences of carbon and nitrogen are completed with hydrogen atoms, halogen, C|-Cô linear, branched, and cyclic alkyl groups, and Cj-Cô linear, branched, and cyclic alkoxy groups, wherein the Cj-Cô linear, branched, and cyclic alkyl groups and the C|-Cô linear, branched, and cyclic alkoxy groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy groups, and carboxylic acid.
3. 3. The compound according to claim 1 or claim 2, a tautomer thereof, a pharmaceutically acceptable sait of the compound, a pharmaceutically acceptable sait of the tautomer, a deuterated dérivative of the compound, a deuterated dérivative of the tautomer, and/or a deuterated dérivative of the sait, wherein R° is chosen from aryl rings, heteroaryl rings, and Cj-C₈ linear, branched, and cyclic alkyl groups, each of which îs optionally substituted with 1-2 substituents independently chosen from halogen, carboxylic acid, Cj-Cô linear, branched, and cyclic alkyl groups, Cj-Cô linear, branched, and cyclic alkoxy groups, aryl rings, and heteroaryl rings.

   613
4. 4. The compound according to any one of claims l to 3, a tautomer thereoi, a pharmaceutically acceptable sait of the compound. a pharmaceutically acceptable sait of the tautomer, a deuterated derîvative ofthe compound, a deuterated derîvative ofthe

   5 tautomer, and/or a deuterated derîvative of the sait, wherein R^ü is chosen from:
5. 5. The compound according to any one of claims l to 4, a tautomer thereof, a pharmaceutically acceptable sait of the compound, a pharmaceutically acceptable sait of lhe tautomer, a deuterated derîvative of the compound, a deuterated derîvative of the

   10 tautomer, and/or a deuterated derîvative of the sait, wherein R¹ is chosen from:

   614

   5
6. 6. The compound according to claim 2, a tautomer thereof, a pharmaceutically acceptable sait of the compound, a pharmaceutically acceptable sait of the tautomer, a deuterated derîvative of the compound, a deuterated derîvative of the tautomer, and/or a deuterated derîvative of the sait, wherein R² is chosen from:
7. 7. The compound according to any one of claims l to 6, a tautomer thereof, a pharmaceutically acceptable sait of the compound, a pharmaceutically acceptable sali of the tautomer, a deuterated derîvative of the compound, a deuterated derîvative of the tautomer, and/or a deuterated derîvative of the sait, wherein each R³ is independently

   15 chosen from hydrogen, deuterium, halogen, Ci-Cô linear alkyl groups, and heterocyclyl groups.
8. 8. The compound according to any one of claims I to 7, a tautomer thereof, a pharmaceutically acceptable sait of the compound, a pharmaceutically acceptable sait of

   615 the tautomer, a deuterated dérivative ofthe compound, a deuterated dérivative ofthe tautomer, and/or a deuterated dérivative of the sait, wherein X’ and X² are independently chosen from hydrogen and halogen.

   5
9. 9. A compound of Fonnula 1-A. I-B, I-C, I-D, I-E, I-F, 1-G, and I-H:

   l-D l-E l-F

   a tautomer thereof, a pharmaceutically acceptable sait of the compound, a 10 pharmaceutically acceptable sait of the tautomer, a deuterated dérivative of the compound, a deuterated dérivative of the tautomer, and/or a deuterated dérivative ofthe sait, wherein:

   R°, R¹, R², R³, and n are defined for compounds of Formula (I)

   X¹and X² are independently chosen from hydrogen and fluorine, or X¹ is fluorine and X² is hydrogen, or X² is fluorine and X¹ is hydrogen, or X¹ and X² are each hydrogen, 15 each of W¹ and W² is independently selected from C and N,

   Y ², Y³, and Y⁴ are independently chosen from

   616 hydrogen.

   cyano, halogen groups,

   Ci-Cô linear, branched, and cyclic alkyl groups,

   C_rC₆ linear, branched, and cyclic alkoxy groups that are optionally substituted with l-4 substituents independently chosen from hydroxy, C|-C₆linear, branched, and cyclic alkyl groups, and C|-C_f,linear, branched, and cyclic alkoxy groups;

   Y ’, Y⁶, Y⁷, and Y⁸ are independently chosen from hydrogen, halogen groups, hydroxy,

   Ci-Cé linear, branched, and cyclic alkyl groups optionally substituted with l -4 independently chosen halogen substituents, and

   Ci-G linear, branched, and cyclic alkoxy groups,

   Y ⁹, Y¹⁰, Y¹¹, Yⁱ², Y¹³, Y¹⁴, Y¹’, and Υ^,ύ are independently chosen from carboxylic acid, hydrogen, halogen groups, Ci-Cô linear, branched, and cyclic alkylsulfonyl groups, Cj-Cô linear, branched, and cyclic alkyl groups optionally substituted with 1-4 independently chosen halogen substituents, and

   Ci-C₆ linear, branched, and cyclic alkoxy groups, Y¹⁷, Y¹⁸, Y¹⁹, Y²⁰, and Y²¹ are independently chosen from hydrogen, carboxylic acid, halogen groups, cyano, hydroxy,

   C|-C(, linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 substituents independently chosen from halogens.

   617 hydroxy, and carboxylic acid, C|-C₍₁ linear, branched, and cyclic alkoxy groups that are optionally substituted with a carboxylic acid group, dihydroxyboryl, sulfonic acid, carboxylic acid optionally esterified with a uronic acid, tetrazolyl groups, aminosulfonyl groups, optionally substituted with l or 2 substituents independently chosen from

   Cj-Cô linear, branched, and cyclic alkyl groups, and

   C|-Cô linear, branched, and cyclic alkylsulfonyl groups with the proviso that, in Formula I-E, at least one of Y¹⁷, Y¹⁸, Y^1J, Y²⁰, and Y is hydrogen.
10. 10. The compound according to claim 9, a tautomer thereof, a pharmaceutically acceptable sait of the compound, a pharmaceutically acceptable sait of the tautomer, a deuterated derîvative of the compound, a deuterated derîvative of the tautomer, and/or a deuterated derîvative of the sait, wherein one or more of Y ,Y ,Y ,Y , and Y is chosen from methyl, methoxy, cyano, fluorine, hydroxy, -CF₃, -B(OH)₂, -SO₂NHMe,

    618
11. 11. A compound chosen from:

    619

    620

    621

    _____F

    622

    623

    624

    625

    626

    627

    628

    629

    630

    109 110 111

    Οχ 0 γΟΗ Y OH Οχ γΟΗ γΑ f-q θ

    Η H / na+A /x H / N-AAA z\

    A X A p a J I W X ’AAN / ^v X II Ί VA > X'-AA'n / ^v

    F F F _____112 113 114 o_x o

    Y OH γΟΗ

    0_x

    Aon

    Jb F F \ f-Ya aS

    H f H [ \^A

    N-aaA a OMe 0A'A A OMe H ^AzA /—OMe

    XXL M- AA A- |R 0 F W v-AA-n 1 ^x—AA-N

    Q b

    F

    F F

    115 116 117

    O_x o

    Y OH γΟΗ

    0_x

    N A N Αχ roh

    MeO'x^J VJj

    H £ H JA O .ⁿAA a OMe aIA N N a OMe ^ναΓα H / N~a\A /—OMe xX £ W ^aA-n A V

    0 J Q

    T F _______F___ ______F_____

    63]

    632

    633

    634

    635

    636

    637

    638

    639

    640

    641

    642

    643

    644

    645

    646

    647

    648

    649

    650

    651

    298 299 300

    0, HO,

    Voh y°

    HO

    A°

    O χΛ rS

    H / H Γ \

    ΑαΧ /-=N ⁿ-aaA i \X Xaa H / ^aA 1 n T A W ' 'AA I ^^AA n X—=_N A^ïA-n^ X——N s ArA A \\ ^faA

    Va \ Λ w

    F

    301 302 303

    HO V° HO V°

    0, v-oh θ €/

    H 'i H 'l CX ⁿ-aaA i ⁿ-aaA i H /

    N I L A__A n 1 A A—A i y A-, IL /\ A Ax LL / \ N l[ Y—k ^-^AA-n X—=_N ^AA^N X-ΞΝ Λ LL / \ n V^_N

    F \

    A^ / Xx

    Wf XX

    304_______________ 305 306

    HO HO,

    X=O AO

    HO

    A° xS fl >X \ / \ LA

    H / H Γ ^ναΆ i ⁿ=a\A i H Γ

    VX XXX vOAA N-AxA 1 n | F L—d

    A'A X—-ΞΝ ^^A-n X-ΞΝ <χ aX IL ⁷ x

    XL A/Ai Xv LAo A^s

    ------ _______\_______

    652

    653

    654

    655

    a tautomer theieof, a pharmaceutically acceptable sait of the compound, a pharmaceutically acceptable sait of the tautomer, a deuterated derivatîve ofthe compound, a deuterated derivatîve of the tautomer, and a deuterated derivatîve ofthe sait.
12. 12. A compound of formula (Γ):

    a tautomer thereof, a pharmaceutically acceptable sait of any ofthe foregoing, and/or a deuterated derivatîve of any of the foregoing;

    656 wherein:

    (i) R⁰'is chosen from (a) C_t-C₈ linear. branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with l-4 R^A'; and (b) 5- to 14-membered aromatic rings optionally substituted with l-4 R^A', wherein each R^A is independently chosen from halogens, cyano, hydroxy, thiol, sulfonic acid, sulfonamide, sulfinamide, amino, amide, 5- to l O-membered aromatic rings, and Cj-C& linear, branched, and cyclic groups, wherein the Ci-Cô linear, branched, and cyclic groups are chosen from alkyl, alkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, alkylsulfonamide, alkylsulfinamide, aminoalkyl, and alkyïamide, and wherein the 5- to 10-membered aromatic rings and C_rC₆ linear, branched, and cyclic groups are optionally substituted with 1-4 substituents selected from halogens and methoxy, and wherein an R^A' group is optionally linked to an R^B' group on an R²' group; (îi) R¹ ' is chosen from (a) hydrogen, (b) C_rC₈ linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 substituents independently chosen from halogens, cyano, hydroxy, and

    C_rC₆ linear, branched, and cyclic groups, wherein the Cj-C₆ linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the C_rC₆ linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and

    Cj-Cô linear, branched, and cyclic alkoxy groups, (c) Ci-C₈ linear, branched, and cyclic alkoxy or cyclic thioalkyl groups optionally substituted with 1-4 substituents independently chosen from halogens, cyano, sulfone,

    657 sulfonamide, hydroxy, and

    C|-C₆linear, branched, and cyclic alkyl groups that are optionally substituted with l-4 halogens;

    (d) C]-C₆ linear, branched, and cyclic alkylsulfonyl groups;

    (e) aminosulfonyl groups, optionally substituted with l or 2 substituents independently chosen from

    C|-C₆ linear, branched, and cyclic alkyl groups;

    (f) C_rC₆ linear, branched, and cyclic alkylsulfonyl amino groups; and (g) phosphine oxide groups, optionally substituted with ] or 2 substituents independently chosen from

    C|-C₆ linear, branched, and cyclic alkyl groups;

    (h) C]-C₆ linear, branched, and cyclic trialkylsilyl groups;

    (iii) R²' is chosen from:

    (iv) X¹ ' and X²' are independently chosen from hydrogen, halogens, cyano, hydroxy, C|-C₆ hnear, branched, and cyclic groups wherein the C_rC₆ linear, branched, and cyclic groups are independently chosen from alkyl, alkoxy, thioalkyl, and aminoalkyl groups, and wherein the Cj-C₆ hnear, branched, and cyclic groups are optionally substituted by 1 -4 20 independently chosen halogens;

    (v) each represents a single or double bond, provided that no more than one is a double bond;

    (vi) each R is independently chosen from hydrogen, halogens, cyano, C_rC₆ linear, branched, and cyclic alkyl groups, and C)-C₆ linear, branched, and cyclic alkoxy groups, 25 wherein the linear, branched, and cyclic alkyl and alkoxy groups are optionally substituted with 1 -4 independently chosen halogens;

    658 (vii) η ' is an integer chosen from 0, l, 2. and 3 ; and (viii) Z , Z', and Z 'are independently chosen from carbon, nitrogen, sulfur, and oxygen, wherein when Z¹', Z²', and/or Z³' are carbon or nitrogen, the valences of carbon and nitrogen are completed with hydrogen atoms.

    13, A compound of formula (Γ):

    a tautomer thereof, a pharmaceutically acceptable sait of any of the foregoing, and/or a deuterated dérivative of any of the foregoing;

    wherein:

    (i) R⁰' is chosen from (a) Ci-C₈ linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 R^A; and (b) 5- to 14-membered aromatic rings optionally substituted with 1-4 R^A', wherein each R^A' is independently chosen from halogens, cyano, hydroxy, thiol, sulfonic acid, sulfonamide, sulfinamide, amino, amide, 5- to 10-membered aromatic rings, and CpCô linear, branched, and cyclic groups, wherein the Cj-Cè linear, branched, and cyclic groups are chosen from alkyl, alkoxy, thioalkyl, alkylsulfoxîde, alkylsulfonyl, alkylsulfonamide, alkylsulfinamide, aminoalkyl, and alkylamide, and wherein the 5- to 10-membered aromatic rings and C|-C₆ linear, branched, and cyclic groups are optionally substituted with 1-4 substituents selected from halogens and methoxy, and wherein an R^A' group is optionally linked to an R^11, group on an R²' group;

    (ii) R¹ ' is chosen from (a) hydrogen, (b) C|-C₈ linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 substituents independently chosen from

    659 halogens, cyano, hydroxy, and C|-C₆ linear, branched, and cyclic groups, wherein the Cj-Cô linear, branched, and cyclic groups are independently chosen from alkyl and alkoxy groups, and wherein the C|-C₆ linear, branched, and cyclic groups are optionally substituted with 1-4 substituents independently chosen from halogens, hydroxy, and

    C|-C&linear, branched, and cyclic alkoxy groups, (c) Ci-Cg linear, branched, and cyclic alkoxy or cyclic thioalkyl groups optionally substituted with 1-4 substituents independently chosen from halogens, cyano, sulfone, sulfonamide, hydroxy, and

    C|-Cô linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 halogens;

    (d) C|-Cô linear, branched, and cyclic alkylsulfonyl groups;

    (e) aminosulfonyl groups, optionally substituted with 1 or 2 substituents independently chosen from

    Cj-Cô linear, branched, and cyclic alkyl groups;

    (0 C1-C₆ linear, branched, and cyclic alkylsulfonyl amino groups; and (g) phosphine oxide groups, optionally substituted with 1 or 2 substituents independently chosen from

    Ci-C₆ linear, branched, and cyclic alkyl groups;

    (h) Ci-C₆ linear, branched, and cyclic trialkylsilyl groups;

    (m) R is chosen from5- and 6-membered aromatic rings comprising 0-4 heteroatoms chosen from O, N, and S, wherein the 5-niembered ring is optionally substituted with 1-4 R^B' groups and the 6-membered ring is optionally substituted with 1-5 R^B' groups, wherein the R^B' groups are independently chosen from optionally substituted amides,

    660 imidazolidine-2,4-dione.

    optionally substituted heterocyclyls, phosphorous acid optionally esterified with a C|-Cô linear, branched, or cyclic alkyl group, di(C_f-C₆)alkylphosphine oxides, (C|-C₆)alkylphosphinic acids optionally esterified with a C^Ce linear, branched, or cyclic alkyl group, halogens, cyano, hydroxy, carboxylic acids optionally esterified with a uronic acid or a Cj-Cô linear, branched, or cyclic alkyl group, oxo, dihydroxylboryl,

    5- and 6-membered aromatic rings comprising 0-4 heteroatoms independently chosen from O, N, and S, optionally substituted with l or 2 substituents independently chosen from C]-C₆ linear, branched, and cyclic alkyl groups that are optionally substituted with l-4 substituents independently chosen from hydroxy, carboxylic acids, pyrrolidin-2-one,

    Cj-Cô linear, branched, and cyclic alkyl groups, and

    Cj-Co linear, branched, and cyclic alkylsuifonyl groups, and

    Cj-Cô linear, branched, and cyclic alkoxy groups, sulfonic acid,

    Cj-Cô linear, branched, and cyclic alkylsuifonyl groups, aminosulfonyl groups, optionally substituted with 1 or 2 substituents independently chosen from

    C]-Cô linear, branched, and cyclic alkyl groups,

    C|-Côlinear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 substituents independently chosen from halogens,

    661 hydroxy, carboxylic acid, and

    C|-Côlinear, branched, and cyclic alkoxy groups,

    C j-C(, linear, branched, and cyclic alkoxy groups that are optionally

    5 substituted with ]-4 substituents independently chosen from halogens, hydroxy, carboxylic acid,

    Ci-Cô linear, branched, and cyclic alkyl groups, and i 0 Ci-Cô linear, branched, and cyclic alkoxy groups, and letrazolyl groups that are optionally substituted with substituents chosen from halogens, hydroxy,

    15 carboxylic acid,

    Cj-Cô linear, branched, and cyclic alkyl groups, and Cj-Cô linear, branched, and cyclic alkoxy groups, wherein 2 adjacent hydrogens on the 5- or 6-membered aromatic ring can be replaced by attachments to a second 5- or 6-membered aromatic ring comprising 020 4 heteroatoms independently chosen from O, N, and S to form a bicyclic R²' group »

    that is optionally substituted with l-6 R groups;

    (iv) X*'and X²'are independently chosen from hydrogen, halogens, cyano, hydroxy, C|-C₆ linear, branched, and cyclic groups wherein the Ci-Cô linear, branched, and cyclic groups are independently chosen from alkyl, alkoxy, thioalkyl, and aminoalkyl groups, 25 and wherein the Ci-C₆linear, branched, and cyclic groups are optionally substituted by l-4 independently chosen halogens;

    (v) each j---represents a single or double bond, provided that no more than one ---is a double bond;

    (vi) each R³' is independently chosen from hydrogen, halogens, cyano, Ci-Cô linear,

    30 branched, and cyclic alkyl groups, and Ci-C₆ linear, branched, and cyclic alkoxy groups, wherein the linear, branched, and cyclic alkyl and alkoxy groups are optionally substituted with 1-4 independently chosen halogens;

    (vii) n' is an înteger chosen from 0, 1,2, and 3; and

    662 (viii) two of Z¹ Z²', and Z³' are nitrogen and the third is chosen from carbon, nitrogen, sulfur, and oxygen, wherein the valences of carbon and nitrogen are completed with hydrogen atoms.
13. 14. Crystalline Compound 33 Form A.
14. 15. Crystalline Compound 33 Form B.
15. 16. Crystalline Compound 33 DCM Solvaté Form A.
16. 17. Crystalline Compound 33 Hydrate Form A.
17. 18. Crystalline Compound 33 MeOH/H₂O Solvate/Hydrate Form A.
18. 19. Crystalline Compound 33 Form C.
19. 20. Crystalline Compound 33 Form D.

    2] . Crystalline Compound 33 Form E.
20. 22. Crystalline Compound 33 Form F.
21. 23. Crystalline Compound 33 Form G.
22. 24. Crystalline Compound 33 Form H.
23. 25. Crystalline Compound 33 Form I.
24. 26. Crystalline Compound 33 THF Solvaté Form A.
25. 27. Crystalline Compound 33 Form J.
26. 28. Crystalline Compound 33 Form K.

    663
27. 29. Crystalline Compound 33 Form L.
28. 30. Crystalline Compound 33 2-MeTHF Solvaté Form A.
29. 31. Crystalline Compound 33 Form M.
30. 32. Crystalline Compound 33 Form N.
31. 33. Crystalline Compound 33 Form O.
32. 34. Crystalline Compound 33 Potassium Sait FormA.
33. 35. Crystalline Compound 33 Potassium Sait FormB.
34. 36. Crystalline Compound 33 Potassium Sait FormC.
35. 37. Substantially amorphous Compound 33.
36. 38. A solid dispersion comprising substantially amorphous Compound 33.
37. 39. The solid dispersion comprising substantially amorphous Compound 33 according to claim 38, further comprising a polymer.
38. 40. The solid dispersion comprising substantially amorphous Compound 33 according to claim 39, wherein the polymer is selected from polyvinylpynOlidone/viny] acetate (PVPVA), hydroxypropylmethylcellulose (HPMC), and hydroxypropylmethylcellulose acetate succînate (HPMCAS).

    4l, The solid dispersion comprising substantially amorphous Compound 33 according to claim 39 or claim 40, wherein substantially amorphous Compound 33 is present in an amount from 30-50%.

    664

    42, The solid dispersion comprising substantially amorphous Compound 33 according to claim 39 or claim 41, wherein substantially amorphous Compound 33 is present in an amount from 50-80%.
39. 43. The solid dispersion comprising substantially amorphous Compound 33 according to any one of claims 39 to 42 prepared as a spray-dried dispersion.
40. 44. A pharmaceutical composition comprising the compound, tautomer, sait, or deuterated dérivative according to any one of claims 1 to 13, crystalline Compound 33 according to any one of claims 14 to 36, substantially amorphous Compound 33 according to claim 37, or the solid dispersion according to any one of claims 38 to 43, and a pharmaceutically acceptable carrier.
41. 45. A compound chosen from the compounds, tautomers, pharmaceutically acceptable salts. and deuterated dérivatives according to any one of claims 1 to 13, crystalline Compound 33 according to any one of claims 14 to 36, substantially amorphous Compound 33 according to claim 37, or the solid dispersion according to any one of claims 38 to 43, or the pharmaceutical composition according to claim 44 for use in treating a patient suffering from alpha-1 antitrypsin deficiency.
42. 46. The compound, solid dispersion, or pharmaceutical composition for use according to claim 45, wherein the patient has a Z mutation in alpha-1 antitrypsin.
43. 47. The compound, solid dispersion, or pharmaceutical composition for use according to claim 45, wherein the patient has an SZ mutation in alpha-1 antitrypsin.
44. 48. The compound, solid dispersion, or pharmaceutical composition for use according to claim 45, wherein the patient is homozygous for Z-mutations in alpha-I antitrypsin.
45. 49. A method for preparing the compound 4-[5-(4-fluorophenyl)-6-tetrahydropyran-4yl-177-pyrrolo[2,3-f]indazoi-7-yl]benzoic acid, the method comprising:

    665 (a) contacting methyl 4-(5-(4-fiuorophcnyl)-I-pivaloyl-6-(tetrahydro-2H-pyran-4yl)-l.5-dihydropyπΌlo[2,3-f]indazol·7-y])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 an organic portion from step (b), adding an alcohol and optionally adding water to the organic portion, and concentrating the mixture by distillation; and (d) isolating the compound 4-[5-(4-fiuorophenyl)-6-tetrahydropyran-4-yl-l//pyrrolo [2,3-f] indazol-7-yl] benzoic acid from the mixture from step (c) and drying the materiai to remove ail water content.
46. 50. The method of claims 49, wherein the method further comprises reacting l -(5-(4fluorophenyl)-7-iodo-6-(tetrahydro-2H-pyran-4-yl)pyrrol o[2,3-f] indazol- 1(5H)-yl)-2,2dimethylpropan-I-one with 4-(methoxycarbonyl)phenyl)boronic acid to form methyl 4-(5(4-fluorophenyl)-l-pivaloyl-6-(tetrahydro-277-pyran-4-y])-l,5-dihydropynOlo[2,3f]indazoI-7-yl)benzoate.
47. 51. The method of claim 50, wherein the method further comprises reacting 1-(5-(4fluoiOphenyl)-6-(tetrahydro-2//-pyran-4-yl)pynOlo[2,3-f]îndazol-l(5//)-y] )-2,2dimethylpropan-l-one with AModosuccinimide to form l-(5-(4-fluorophenyl)-7-iodo-6(tetrahydro-2H-pyran-4-yl)pynOlo[2,3-f]indazol-l(5H)-yl)-2,2-dimethylpropan-I-one.
48. 52. I he method of claim 51, wherein the method further comprises reacting 5-(4fluorophenyl)-6-(tetrahydro-2//-pyran-4-yl)-l,5-dihydropyrrolo[2,3-f]indazole with trimethylacetyl chloride to form 1 -(5-(4-fluorophenyl)-6-(tetrahydro-2//-pyran-4yj)pyrrolo[2,3-f]indazol-I(5/7)-yl)-2,2-dimethylpropan-l -one.
49. 53. The method of claim 52, wherein the method further comprises reacting 7V-(4fluorophenyl)-6-((tetrahydro-2/f-pyran-4-yl)ethynyl)-l//-indazol-5-amine with a second acid to form 5-(4-fluorophenyl)-6-(tetrahydro-2/7-pyran-4-y 1)-1,5-dihydropyrrolo[2,31] indazole.
50. 54. The method of claim 53, wherein the method further comprises reacting 5-bromo6-iodo-l//-indazole with trimethyI((tetrahydro-2//-pyran-4-yl)ethnyI)silane to form 5bromo-6-((tetrahydro-2//-pyran-4-yl)ethynyl)-l //-indazole.

    666
51. 55. A compound selected from:

    5-bromo-6-((teirahydro-2/7-pyran-4-yl)ethynyl)-l /Aindazole (C2)

    A-(4-fluorophenyl)-6-((letrahydeo-2//-pyran-4-yl)ethynyI-l/7-indazole-5-amine (02)

    5-(4fluorophenyl)-6-(ÎetrahydrO'2H’pyran-4-yl)-l_;5-dihydropyrrolo[2,3-f]indazole (C13)

    l-(5-(4-fluoropheny])-6-(tetrahydro-2H-pyran-4-y l)pyrrolo[2,3-f] indazol-l(5H)-yl)-2_s2-

    l-(5-(4-fluorophenyl)-7-iûdo-6-(tetrahydro-2H-pyran-4-yl )pyrrolo[2,3-f] indazol-l(5H)yl)-2,2-dimethylpropan-l-one (S4)

    667

    methyl 4-(5-(4-fluorophenyl)-]-pivaloyl-6-(tetrahydro-2H-pyran-4-yl)-l,5dihydropynOlo[2,3-fJindazol-7-yl)benzoate (C58)

    F
52. 56. Spray-dried neat amorphous Compound 33.