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US-12624028-B2 - 1H-pyrazolo[4,3-G]isoquinoline and 1H-pyrazolo[4,3-g]quinoline derivatives as alpha-1-antitrypsin modulators for treating alpha-1-antitrypsin deficiency (AATD)

US12624028B2US 12624028 B2US12624028 B2US 12624028B2US-12624028-B2

Abstract

1H-pyrazolo[4,3-g]isoquinoline and 1H-pyrazolo[4,3-g]quinoline derivatives as alpha-1-antitrypsin modulators for treating alpha-1-antitrypsin deficiency (AATD).

Inventors

  • Simon Giroux
  • Emily Elizabeth ALLEN
  • Jinwang Xu
  • Michael Paul Deninno
  • Qing Tang
  • Diane Marie BOUCHER
  • Lev T.D. Fanning
  • Amy B. HALL
  • Dennis James Hurley
  • Mac Arthur Johnson, JR.
  • John Patrick Maxwell
  • Philippe Marcel Nuhant
  • Rebecca Jane Swett
  • Timothy Lewis TAPLEY
  • Stephen A. Thomson
  • Veronique Damagnez
  • Kevin Michael Cottrell
  • Upul Keerthi Bandarage
  • Pedro Manuel GARCIA BARRANTES
  • Yusheng Liao
  • Zachary Gale-Day
  • Wenxin Gu
  • Alexander S. KARNS
  • Hu ZHANG

Assignees

  • VERTEX PHARMACEUTICALS INCORPORATED

Dates

Publication Date
20260512
Application Date
20210402

Claims (20)

  1. 1 . A compound represented by Formula II a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: W 1 and W 2 are each independently selected from —C═O, —CR 2 , N, and —NR 2 , wherein: when W 1 is —CR 2 , then W 2 is N; when W 2 is —CR 2 , then W 1 is N; when W 1 is —C═O, then W 2 is —NR 2 ; and when W 2 is —C═O, then W 1 is —NR 2 (h) is a double bond except that when one of W 1 and W 2 is —C═O, then (h) is a single bond; Ring A is C 3 -C 12 carbocyclyl, 3 to 12-membered heterocyclyl, C 6 or C 10 aryl, or 5 to 10-membered heteroaryl; R 1 is halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —C(═O)R z , —C(═O)OR z , —C(═O)NR w R x , —NR w R x , —NR w C(═O)R z , —NR w C(═O)OR z , —NR w C(═O)NR x R y , —OR z , —OC(═O)R z , —OC(═O)NR w R x , S(═O) 2 R z , C 3 -C 6 cycloalkyl, or 3 to 6-membered heterocyclyl; wherein: the C 1 -C 6 alkyl, the C 3 -C 6 cycloalkyl, or the 3 to 6-membered heterocyclyl of R 1 is optionally substituted with 1 to 3 groups independently selected from —OR z , C 1 -C 3 haloalkyl, —CN, and halogen; and R w , R x , R y , and R z are each independently hydrogen or C 1 -C 4 alkyl; X 1 and X 2 are each independently hydrogen, halogen, —CN, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 3 -C 6 cycloalkyl, or 5 or 6-membered heteroaryl; R 2 is hydrogen, halogen, wherein: T is absent, or is selected from —O—, —OCH 2 —, —NH—, —NS(═O) 2 CH 3 , —S—, and —CH 2 —; Y is selected from C 1 -C 6 alkyl, —(CR a R a ) p COOH, —(CR a R a ) p NR b S(═O) 2 (CR c R c ) q OH, —(CR a R a ) p C(═O)NR b (CR c R c ) g COOH, and —(CR a R a ) p (O)(CR c R c ) q COOH; wherein: R a , for each occurrence, is independently hydrogen, halogen, —OH, or C 1 -C 4 alkyl optionally substituted with 1 to 3 groups independently selected from halogen and —OH; or alternatively, when R a , for each occurrence, is independently C 1 -C 4 alkyl, two R a groups together with their intervening carbon atom form cyclopropyl or cyclobutyl; R b and R c , for each occurrence, are each independently hydrogen or C 1 -C 2 alkyl; and p and q are each independently an integer selected from 1 and 2; Ring B is C 3 -C 12 carbocyclyl, 3 to 12-membered heterocyclyl, C 6 or C 10 aryl, or 5 to 10-membered heteroaryl; R 3 is —C(═O)OR d ; wherein R d is C 1 -C 4 alkyl optionally substituted with —OC(O)R e , —OC(═O)OR e , or —OP(═O)R f R f ; wherein: R e , for each occurrence, is independently hydrogen or —CH 3 ; R f , for each occurrence, is independently —OH, —CH 3 , or —OCH 3 ; R k is halogen, —CN, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 2 haloalkoxy, or O—(C 3 -C 6 cycloalkyl); R m , for each occurrence, is independently halogen, —CN, ═O, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —C(═O)R r , —C(═O)OR r , —C(═O)NR p R q , —C(═O)NR p OR r , —NR p R q , —NR p C(═O)R r , —NR p S(═O) 2 R r , —OR r , S(═O) 2 R r , —S(═O) 2 NR p R q , —P(═O)R s R t , C 3 -C 6 cycloalkyl, 3 to 6-membered heterocyclyl, phenyl, or 5 or 6-membered heteroaryl, wherein the C 1 -C 6 alkyl, the phenyl, or the 5 or 6-membered heteroaryl of R m is optionally substituted with 1 to 3 groups independently selected from halogen, CN, —C(═O)OR r , —NR p R q , and —OR r ; and wherein the C 3 -C 6 cycloalkyl or the 3 to 6-membered heterocyclyl of R m is optionally substituted with 1 to 3 groups independently selected from halogen, CN, ═O, —C(═O)OR r , —NR p R q , and —OR r ; wherein R p and R q , for each occurrence, are each independently hydrogen or C 1 -C 4 alkyl optionally substituted with 1 to 3 groups independently selected from —OH, —OCH 3 , —OC 2 H 5 , and —COOH; wherein R r , for each occurrence, is independently hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or 3 to 6-membered heterocyclyl; wherein the C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or 3 to 6-membered heterocyclyl of R r is optionally substituted with 1 to 3 groups independently selected from —OH, —OCH 3 , —OC 2 H 5 , —CH 2 OH, —C(═O)OH, —(O)C(═O)OH, and —(O)P(═O)(OH) 2 ; and wherein R s and R t , for each occurrence, are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or —OH; k and m are each independently an integer selected from 0, 1, 2, 3, 4, and 5; and n is an integer selected from 0and 1.
  2. 2 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein the compound is represented by Formula IIIa, IIIb, IIIc, or IIId: wherein: Ring A is optionally substituted with R k and Ring A is 5 or 6-membered carbocyclyl, phenyl, or 5 or 6-membered heteroaryl; R 1 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —C(═O)OR z , —C(═O)NR w R x , —NR w R x , —OR z , —S(═O) 2 R z , C 3 -C 6 cycloalkyl, or 3 to 6-membered heterocyclyl; wherein: the C 1 -C 6 alkyl, the C 3 -C 6 cycloalkyl, or the 3 to 6-membered heterocyclyl of R 1 is optionally substituted with 1 to 3 groups independently selected from —OR z and halogen; and R w , R x , and R z are each independently hydrogen or C 1 -C 4 alkyl; X 1 and X 2 are each independently hydrogen, halogen, —CN, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 2 haloalkoxy or C 3 -C 4 cycloalkyl; R 2 is as defined in claim 1 , except when R 2 is Ring B is optionally substituted with R m and Ring B is C 4 -C 9 carbocyclyl, phenyl, 4 to 9-membered heterocyclyl, or 5 to 6-membered heteroaryl; R 3 is absent or is —C(═O)O(CH 2 ) 2 (O)P(═O)(OH) 2 ; and R k is halogen, —CN, —CH 3 , C 1 haloalkyl, or —OCH 3 .
  3. 3 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein the compound is represented by Formula IVa, IVb, or IVc: wherein X 1 is hydrogen, halogen, —OH 3 , —OHF 2 , —OH 2 F, or —OCH 3 .
  4. 4 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein the compound is represented by Formula Va, Vb, or Vc: wherein: R 1 is C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —C(═O)OR z , —C(═O)NR w R x , —NR w R x , —OR z , —S(═O) 2 R z , cyclopropyl, cyclobutyl or 5 or 6-membered heterocyclyl; wherein: the C 1 -C 4 alkyl, the cyclopropyl, the cyclobutyl, or the 5 or 6-membered heterocyclyl of R 1 is optionally substituted with 1 to 3 groups independently selected from —OR z and halogen; and R w , R x , and R z are each independently hydrogen or C 1 -C 2 alkyl; and T is absent, or is selected from —O—, —OCH 2 —, —NH—, and —CH 2 —.
  5. 5 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein Ring A is optionally substituted with R k and Ring A is phenyl, cyclohexenyl, 3,6-dihydro-2H-pyranyl, pyridinyl, pyridazinyl, thiophenyl, or pyrazolyl.
  6. 6 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein Ring A is optionally substituted with R k and Ring A is selected from:
  7. 7 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein Ring A is optionally substituted with R k and Ring A is selected from
  8. 8 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein when R 2 is Ring B is optionally substituted with R m and Ring B is selected from isoindolinyl, azaspiro[3.4]octanyl, spiro[3.3]heptanyl, azaspiro[3.3]heptanyl, oxaspiro[3.3]heptanyl, azabicyclo[3.2.0]heptanyl, phenyl, cyclohexenyl, cyclohexyl, pyridinyl, piperidinyl, morpholinyl, tetrahydro-2H-pyranyl, thiazolyl, pyrazolyl, furanyl, tetrahydrofuranyl, cyclopentyl, bicyclo[1.1.1]pentanyl, pyrrolidinyl, cyclobutyl, azetidinyl, and cyclopropyl.
  9. 9 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R 2 is and Ring B is optionally substituted with R m and Ring B is selected from:
  10. 10 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R 2 is and Ring B is optionally substituted with R m and Ring B is selected from:
  11. 11 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R m , for each occurrence, is independently halogen, —CN, ═O, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, —C(═O)R r , —C(═O)OR r , —C(═O)NR p R q , —C(═O)NR p OR r , —NR p R q , —NR p C(═O)R r , —NR p S(═O) 2 R r , —OR r , S(═O) 2 R r , —S(═O) 2 NR p R q , —P(═O)R s R t , or 5 or 6-membered heterocyclyl; wherein: the C 1 -C 6 alkyl of R m is optionally substituted with 1 to 3 groups independently selected from —C(═O)OH, —C(═O)OCH 3 , —C(═O)OC 2 H 5 , —OH, —OCH 3 , and —OC 2 H 5 ; and the 5 or 6-membered heterocyclyl of R m is optionally substituted with 1 to 3 groups independently selected from halogen, ═O, —C(═O)OH, and —OH; wherein: R p and R q , for each occurrence, are each independently hydrogen or C 1 -C 3 alkyl optionally substituted with 1 to 3 groups independently selected from —OH, —OCH 3 , and —C(═O)OH; R r , for each occurrence, is independently hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocyclyl; wherein the C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocyclyl of R r is optionally substituted with 1 to 3 groups independently selected from —OH, —OCH 3 , —OC 2 H 5 , —C(═O)OH, —(O)C(═O)OH, and —(O)P(═O)(OH) 2 ; and R s and R t , for each occurrence, are each independently hydrogen, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, or —OH.
  12. 12 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R m , for each occurrence, is independently halogen, CN, =O, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —C(═O)R r , —C(═O)OR r , —C(═O)NR p R q , —C(═O)NR p OR r , —NR p R q , —NR p C(═O)R r , —NR p S(═O) 2 R r , —OR r , S(═O) 2 R r , —S(═O) 2 NR p R q , —P(═O)R s R t , imidazolidinyl, or morpholinyl; wherein: the C 1 -C 4 alkyl of R m is optionally substituted with 1 to 3 groups independently selected from —C(═O)OH, —C(═O)OCH 3 , —C(═O)OC 2 H 5 , —OH, —OCH 3 , and —OC 2 H 5 ; and the imidazolidinyl or the morpholinyl of R m is optionally substituted with 1 to 3 groups independently selected from oxo (=O) and —OH; wherein: R p and R q , for each occurrence, are each independently hydrogen or C 1 -C 3 alkyl optionally substituted with 1 to 3 groups independently selected from —OH, —OCH 3 , and —C(═O)OH; R r , for each occurrence, is independently hydrogen, C 1 -C 2 alkyl, cyclopropyl, oxetanyl, or azetidinyl; wherein the C 1 -C 2 alkyl, cyclopropyl, oxetanyl, or azetidinyl of R r is optionally substituted with 1 to 3 groups independently selected from —OH, —CH 2 OH, —C(═O)OH, and —(O)P(═O)(OH) 2 ; and R s and R t , for each occurrence, are each independently —CH 3 , —OCH 3 , or —OH.
  13. 13 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R m , for each occurrence, is independently selected from —COOH, —C(═O)CH(OH)CH 3 , F, —CH 3 , —C(═O)NH 2 , —C(═O)NH(OCH 3 ), S(═O) 2 NH 2 , —NHS(═O) 2 CH 3 , ═O, —OH, —P(═O)(CH 3 ) 2 , —P(═O)(OH) 2 , —P(═O)(OCH 3 ) 2 , —OH, imidazolidin-4-yl, —CH 2 OH, —NHCH 3 , morpholin-4-yl, —(C═O)NHCH(CH 3 )CH 2 OH, —C(═O)N(CH 3 )CH(CH 3 )CH 2 OH, —NCH 3 C(═O)CH(OH)CH 3 , —C(═O)CH(CH 3 )CH 2 OH, —C(═O)CH(OH)CH 2 OH, —C(═O)(hydroxymethyl)oxetan-3-yl, —C(═O)(hydroxy)cyclopropyl, —C(═O)CH(OH)CH 3 , —C(═O)OCH 3 , —OCH 3 , —CH 2 COOH, —CN, —OCH 2 COOH, —OCH(CH 3 )COOH, —CH(CH 3 )COOH, Cl, S(═O) 2 CH 3 , S(═O) 2 NHCH 3 , —CH 2 C(═O)OC 2 H 5 , —C(═O)OCH 2 (O)P(═O)(OH) 2 , —C(═O)NHCH(CH 3 )COOH, —C(═O)NHCH 3 , —C(═O)(3-hydroxyazetidin-1-yl), and —C(═O)(morpholin-4-yl).
  14. 14 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein at least one occurrence of R m is —COOH, —CH 2 COOH, —OCH 2 COOH, —OCH(CH 3 )COOH, —CH(CH 3 )COOH, —C(═O)OCH 2 (O)P(═O)(OH) 2 , or —C(═O)NHCH(CH 3 )COOH.
  15. 15 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein the compound is represented by Formula VIa, VIb, or VIc:
  16. 16 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R 1 is C 1 -C 3 alkyl, C 1 -C 3 alkoxy, —C(═O)OR z , —C(═O)NR w R x , —NR w R x , —OR z , —S(═O) 2 R z , cyclopropyl, cyclobutyl, or a 6-membered heterocyclyl; wherein: the C 1 -C 3 alkyl, the cyclopropyl, the cyclobutyl, or the 6-membered heterocyclyl of R 1 is optionally substituted with 1 to 3 groups independently selected from —OH, —OCH 3 , C 1 -C 2 haloalkyl, —CN, and halogen; and R w , R x , R y , and R z are each independently hydrogen or —CH 3 .
  17. 17 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R 1 is —C(CH 3 ) 2 , —CF 3 , —CH 2 C(CH 3 ) 2 OCH 3 , —C(CH 3 ) 2 CH 2 OH, —OCH 3 , —O(CH)(CH 3 ) 2 , —C(═O)OCH 3 , —C(═O)N(CH 3 ) 2 , N(CH 3 ) 2 , —S(═O) 2 CH 3 , S(═O) 2 C 2 H 5 , —S(═O) 2 CH(CH 3 ) 2 , tetrahydro-2H-pyran-4-yl, cyclopropyl, or cyclobutyl; and wherein the cyclopropyl or the cyclobutyl of R 1 is optionally substituted with —OH, —OCH 3 , or —CF 3 .
  18. 18 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein the compound is represented by Formula VIIa, VIIb, VIIc, VIId, VIIe, or VIIf:
  19. 19 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein the compound is represented by Formula VIIIa, VIIIb, or VIIIc: wherein: Ring A is optionally substituted with R k and Ring A is phenyl or 5 or 6-membered heteroaryl; T is absent, or is selected from —O—, —NH—, and —CH 2 —; Y is C 1 -C 2 alkyl, —(CR a R a ) p COOH, —(CR a R a ) p NR b S(═O) 2 (CR c R c ) q OH, —(CR a R a ) p C(═O)NR b (CR c R c ) q COOH, or —(CR a R a ) p (O)(CR c R c ) q COOH; wherein: R a , for each occurrence, is independently hydrogen, —OH, —CH 3 , or —CH 2 OH; and R b and R c , for each occurrence, are each independently hydrogen or —CH 3 .
  20. 20 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein is —NHCH 3 , —CH 2 COOH, —(CH 2 ) 2 COOH, —CH(CH 3 )CH 2 COOH, —NHCH(CH 3 )COOH, —OCH 2 COOH, —O(CH 2 ) 2 (O)CH 2 COOH, —CH 2 CH(CH 3 )COOH, —OCH(CH 3 )C(═O)NHCH 2 COOH, or —OCH(CH 2 OH)CH 2 NHS(═O) 2 (CH 2 ) 2 OH.

Description

This application claims the benefit of priority of U.S. Provisional Application No. 63/004,719, filed Apr. 3, 2020, the contents of which are incorporated by reference herein in their entirety. The disclosure provides compounds that are capable of modulating alpha-1 antitrypsin (AAT) activity and methods of treating alpha-1 antitrypsin deficiency (AATD) by administering one or more such compounds. AATD is a genetic disorder characterized by low circulating levels of AAT. While treatments for AATD exist, there is currently no cure. AAT is produced primarily in liver cells and secreted into the blood, but it is also made by other cell types including lung epithelial cells and certain white blood cells. AAT inhibits several serine proteases secreted by inflammatory cells (most notably neutrophil elastase [NE], proteinase 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 individuals 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 consequence 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; and Ogushi et al. J Clin Invest. 1987; 80(5):1366-74). The accumulation of polymerized Z-AAT protein within hepatocytes results in a gain-of-function cytotoxicity that can result in cirrhosis or liver cancer later in life and neonatal liver disease in 12% of patients. This accumulation may spontaneously remit but can be fatal in a small number of children. The deficiency of circulating AAT results in unregulated protease activity that degrades lung tissue over time, resulting in emphysema, a form of chronic obstructive pulmonary disease (COPD). This effect is severe in PiZZ individuals and typically manifests in middle age, resulting in a decline in quality of life and shortened lifespan (mean 68 years of age) (Tanash et al. Int J Chron Obstruct Pulm Dis. 2016; 11:1663-9). The effect is more pronounced in PiZZ individuals who smoke, resulting in an even further shortened lifespan (58 years). (Piitulainen and Tanash, COPD 2015; 12(1):36-41). PiZZ individuals 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 milder form of AATD is associated with the SZ genotype in which the Z-allele is 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 result is clinically significant lung disease but not liver disease. (Fregonese and Stolk, Orphanet J Rare Dis. 2008; 33:16). As with the ZZ genotype, the deficiency of circulating AAT in subjects with the SZ genotype results in unregulated protease activity that degrades lung tissue over time and can result in emphysema, particularly in smokers. The current standard of care for AAT deficient individuals who have 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 have 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 delaying progression of disease, augmentation does not restore the normal physiological regulation of AAT in patients and efficacy has been difficult 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-function of the Z-allele. Thus, there is a continuing need for new and more effective treatments for AATD. One aspect of the disclosure provides a compound of Formula I: or tautomer thereof, deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Z1, Z2, and Z3 are each independently N, —NH, or —CH; provided that at least one of Z1, Z2, and Z3 is N or —NH; V1 and V2 are each selected from C and N; W1 and W2 are each selected from —C═O, —CR2, N, and —NR2, whe