BORONIC ACID DERIVATIVES AND THERAPEUTIC USES THEREOF

• US 20170136047A1
• Filed: 06/29/2015
• Published: 05/18/2017
• Est. Priority Date: 07/01/2014
• Status: Active Grant

• Current Assignee: Qpex Biopharma, Inc.
• Original Assignee: Rempex Pharmaceuticals, Inc (Melinta Therapeutics, Inc.)
• Inventors: Rodny, Olga, Reddy, Raja K., Glinka, Tomasz, Totrov, Maxim, Hecker, Scott
• Granted Patent: US 10,206,937 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Disclosed herein are antimicrobial compounds compositions, pharmaceutical compositions, the use and preparation thereof. Some embodiments relate to boronic acid derivatives and their use as therapeutic agents.

Claims

1. A compound having the structure of Formula (I):

2. The compound of claim 1, wherein:

G is selected from the group consisting of —

NR¹R², —

N₃, —

C(O)NR¹R², —

S(O)₂NR¹R², —

SR³, —

OR³, —

CH₂NR¹C(O)R⁵, —

C(═

NOR³)—

X, C(═

NOR³)—

Z, —

C(O)OR³, —

C(O)NR¹(OR³), —

NR¹(OR³), —

NR¹C(O)R⁵, —

NR¹C(O)NR²R^1a, —

NR¹C(O)OR³, —

NR¹S(O)₂R³, —

NR¹S(O)₂NR²R^1a, —

NR¹NR²R^1a, —

C(O)NR¹NR²R^1a, —

S(O)₂NR¹NR²R^1a, —

C(═

NR¹)R⁵, —

C(═

NR¹)NR²R^1a, —

NR¹CR⁵(═

NR²), —

NR¹C(═

NR²)NR^1aR^2a, optionally substituted C_1-10 alkyl, optionally substituted C_2-10alkenyl, optionally substituted C_2-10alkynyl, optionally substituted C_3-7 carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C_6-10aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C_1-6alkylene-C_3-7carbocyclyl, optionally substituted C_1-6alkylene-5-10 membered heterocyclyl, optionally substituted C_1-6alkylene-C_6-10aryl, and optionally substituted C_1-6alkylene-5-10 membered heteroaryl;

R⁷ is present 1 to 5 times and each R⁷ is independently selected from the group consisting of —

H, —

OH, halogen, —

CF₃, C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆ heteroalkyl, C₃-C₇ carbocyclyl, 5-10 membered heterocyclyl, aryl, 5-10 membered heteroaryl, cyano, C₁-C₆ alkoxy(C₁-C₆)alkyl, aryloxy, sulfhydryl (mercapto), and —

(CH₂)_m—

Y′

—

(CH₂)_pM′

;

M′

is selected from the group consisting of —

C(O)NR¹R²;

—

C(O)NR¹OR³;

—

NR¹C(O)R⁵;

—

NR¹C(O)NR²R^1a;

—

NR¹C(O)OR³;

—

NR¹S(O)₂R³;

—

NR¹S(O)₂NR²R^1a;

—

C(═

NR¹)R⁵;

—

C(═

NR¹)NR²R^1a;

—

NR¹CR⁵(═

NR²);

—

NR¹C(═

NR²)NR^1aR^2a;

CF₃, C_1-4 alkyl optionally substituted with 0-2 substituents selected from the group consisting, —

OR³, —

NR¹R², halogen, —

C(O)NR¹R², and —

NR¹C(O)R⁵;

C_3-10 cycloalkyl optionally substituted with 0-2 substituents selected from the group consisting of C_1-4 alkyl, —

OR³, —

NR¹R², halogen, —

C(O)NR¹R², and —

NR¹C(O)R⁵;

C_6-10 aryl optionally substituted with 0-2 substituents selected from the group consisting of C_1-4 alkyl, —

OR³, —

NR¹R², halogen, —

C(O)NR¹R², and —

NR¹C(O)R⁵;

5 to 10 membered heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of C_1-4 alkyl, —

OR³, —

NR¹R², halogen, —

C(O)NR¹R², and —

NR¹C(O)R⁵; and

4 to 10 membered heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of C_1-4 alkyl, —

OR³, —

NR¹R², halogen, —

C(O)NR¹R², and —

NR¹C(O)R⁵;

R is selected from the group consisting of —

H, —

C_1-9alkyl, —

CR⁵R⁶OC(O)C_1-9alkyl, —

CR⁵R⁶OC(O)OC_1-9alkyl, and

3. The compound of claim 1, wherein G is selected from the group consisting of —

NR¹R², —

N₃, —

C(O)NR¹R², —

S(O)₂NR¹R², —

SR³, —

OR³, —

CH₂NR¹C(O)R⁵, —

C(═

NOR³)—

X, C(═

NOR³)—

Z, —

C(O) OR³, —

C(O)NR¹(OR³), —

NR¹(OR³), —

NR¹C(O)R⁵, —

NR¹C(O)NR²R^1a, —

NR¹C(O)OR³, —

NR¹S(O)₂R³;

—

NR¹S(O)₂NR²R^1a, —

NR¹NR²R^1a, —

C(O)NR¹NR²R^1a, —

S(O)₂NR¹NR²R^1a, —

C(═

NR¹)R⁵, —

C(═

NR¹)NR²R^1a, —

NR¹CR⁵(═

NR²), —

NR¹C(—

NR²)NR^1aR^2a, optionally substituted C_1-10 alkyl, optionally substituted C_2-10alkenyl, optionally substituted C_2-10alkynyl, optionally substituted C_3-7 carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C_6-10aryl, and optionally substituted 5-10 membered heteroaryl.

4. The compound of claim 1, wherein each R¹¹ is independently selected from C₁-C₆ alkyl;

haloC_1-6alkyl;

—

OR³;

—

C_1-6alkylene-COOR³;

—

SR³;

halogen;

—

CO—

C_1-4alkyl;

C(O)NR¹R²;

—

NR¹R²;

—

NR¹(CH₂)_0-4COR⁵;

—

NR¹(CH₂)_0-4C(═

NR²)R⁵;

—

NR¹—

CH—

[(CH₂)_0-4—

NR^1aR^2a]₂;

—

NR¹—

(CH₂)_1-5—

R³;

—

NR¹(CH₂)_1-4—

NR^1aR^2a;

—

N[(CH₂)_1-4—

NR¹R²]₂;

—

S(CH₂)_0-4C(═

NR¹)R⁵;

—

S(CH₂)_1-4—

R³;

—

S(CH₂)_0-4—

NR¹R²;

—

S—

CH—

[(CH₂)_0-4—

NR¹R²]₂;

—

S[(CH₂)_1-4—

NR¹R²]₂;

—

S(CH₂)_0-4-3-10 membered heterocyclyl;

—

S(CH₂)_0-4-3-10 membered heterocyclyl-NR¹R²;

—

S(CH₂)_0-4-5-10 membered heteroaryl-NR¹R²;

—

S(O)₂NR¹R²; and

—

O—

C_1-6alkylene-NR¹R²;

C_3-7 carbocylcyo optionally substituted with halo, amine, cyano, C₁-C₆ alkyl;

C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy;

3-10 membered heterocyclyl optionally substituted with halo, amine, cyano, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy;

6 to 10 membered aryl optionally substituted with halo, amine, cyano, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy; and

5-10 membered heteroaryl optionally substituted with halo, amine, cyano, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy.

5. The compound of claim 1, wherein Y is —

CH₂—

, —

S(O)—

, —

S(O)₂—

, —

O—

, —

NH—

, or —

S—

.

6. The compound of claim 1, wherein R^d is —

OH and X^a is —

CH₂.

8. The compound of claim 1, wherein R^a is selected from the group consisting of optionally substituted —

C_1-6 alkyl, —

OH, —

C(O)OR, optionally substituted —

O—

C_1-6 alkyl, —

NR¹R², —

N(OR³)R², optionally substituted —

S—

C_1-6 alkyl, —

C(O)NR¹R², —

S(O)₂NR¹R², CN, optionally substituted —

S(O)—

C_1-6 alkyl, and optionally substituted —

S(O)₂—

C_1-6 alkyl, and R^b is selected from the group consisting of —

H, halogen, optionally substituted —

C_1-6 alkyl, —

OH, —

C(O)OR, optionally substituted —

O—

C_1-6 alkyl, —

NR¹R², —

N(OR³)R², optionally substituted —

S—

C_1-6 alkyl, —

C(O)NR¹R², —

S(O)₂NR¹R², —

CN, optionally substituted —

S(O)—

C_1-6 alkyl, and optionally substituted —

S(O)₂—

C_1-6 alkyl.

10. The compound of claim 1, wherein R^b is —

OH and R^c is —

OH.

12. The compound of claim 1 having the structure of Formula (I′

);

13. The compound of claim 1, having the structure of Formula (I-1) or Formula (I-2):

14. The compound of claim 1, wherein the two adjacent R⁷ together with any intervening atoms form a 5-8 membered heteroaryl ring or wherein the two adjacent R⁷ together with any intervening atoms form an imidazole ring.

16. The compound of claim 1, wherein R⁸ is H and R⁹ is H and n is 0 or 1.

18. The compound of claim 6, wherein:

Y is selected from the group consisting of —

S—

, —

O—

, —

CH₂—

, and —

NH—

;

G is selected from the group consisting of —

C(O)NR¹R²;

—

C(O)NR¹OR³;

NR¹C(O)R⁵;

—

NR¹C(O)NR²R^2a;

—

NR¹C(O)OR³;

—

NR¹S(O)₂R³;

—

NR¹S(O)₂NR²R^1a;

—

C(═

NR¹)R⁵;

—

C(═

NR¹)NR²R^1a;

—

NR¹CR⁵(═

NR⁵);

—

NR¹C(═

NR²)NR^1aR^2a;

C_6-10aryl optionally substituted with 0-2 substituents selected from the group consisting of C_1-4 alkyl, —

OR³, —

C_1-6alkylene-COOR³, —

SR³, —

NR¹R², halogen, —

C(O)NR¹R², and —

NR¹C(O)R⁵;

5-10 membered heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of C_1-4 alkyl, —

OR³, —

C_1-6alkylene-COOR³, —

SR³, —

NR¹R², halogen, —

C(O)NR¹R², and —

NR¹C(O)R⁵; and

5-10 membered heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of C_1-4 alkyl, —

OR³, —

C_1-6alkylene-COOR³, —

SR³, —

NR¹R², halogen, —

C(O)NR¹R², and —

NR¹C(O)R⁵;

R is selected from a group consisting of —

H, —

C_1-9alkyl, —

CR⁵R⁶OC(O)C_1-9alkyl, and

19. The compound of claim 16, having the structure of Formula (Ia), (Ib), (Ic), or (Id)

25. The compound of claim 13, wherein:

Y is —

O—

or —

S—

;

G is selected from the group consisting of phenyl, imidazole, pyrazole, triazole, tetrazole, thiazole, thiadiazole, oxazole, oxadiazole, isoxazole, isothiazole, pyridine, pyrazine, pyrimidine, pyridazine, azetidine, and pyrazine, each optionally substituted by 0-2 substituents selected from the group consisting of C_1-4 alkyl, —

OR³, —

C_1-6alkylene-COOR³, —

SR³, —

NR¹R², halogen, —

C(O)NR¹R², and —

NR¹C(O)R⁵, wherein R¹, R² and R⁵ in G are independently selected from —

H and —

C_1-4alkyl; and

J, L and M are CR⁷.

28. The compound of claim 1, wherein the compound of formula (I) has the structure of formula (Ie) or (If):

30. The compound of claim 1, wherein G is a 5-10 membered heteroaryl or a 3-10 membered heterocyclyl, and the heteroaryl or heterocyclyl is optionally substituted with one or more R¹⁰.

35. The compound of claim 30, wherein G is selected from thiadiazole, thiazole, imidazole, triazole, azetidine or piperazine, each optionally substituted with one or more R¹⁰.

37. The compound of claim 1, wherein G is selected from

39. The compound of claim 1, wherein R¹⁰ is R¹¹, CH₂R¹¹, (CH₂)₂R¹¹, (CH₂)₃R¹¹, or (CH₂)₄R¹¹.

45. The compound of claim 1, wherein G is thiadiazole;

thiadiazole optionally substituted with —

NR¹R² or —

NR¹C(O)R⁵, wherein R¹, R² and R⁵ in G are independently —

H or —

C_1-4alkyl;

triazole optionally substituted with —

NR¹R², wherein R¹ and R² in G are independently —

H or —

C_1-4alkyl;

triazole optionally substituted with a C_1-4 alkyl;

triazole optionally substituted with —

C_1-6alkylene-COOH;

triazole optionally substituted with (CH₂)₃—

COOH;

tetrazole optionally substituted with methyl;

pyridine;

thiazole;

phenyl;

or azetidine.

56. The compound of claim 13, wherein:

Y is —

S—

or —

CH₂—

;

n is 1 or 2;

G is —

C(O)NR¹R²; and

J, L and M are CR⁷.

58. The compound of claim 1, wherein the compound of formula (I) has the structure of formula (Ig) or (Ih):

59. The compound of claim 58, wherein Z¹ is S;

wherein each Z² and Z³ are independently N, NR¹², or CR¹²; and

wherein Z⁴ is N or CR¹².

62. The compound of claim 58, wherein Z¹ to Z⁴ are selected to form a five membered aromatic ring selected from the group consisting of

63. The compound of claim 58, wherein R¹² is H or R¹² is R¹¹;

and wherein R¹¹ is C₁-C₆ alkyl, C_1-4 alkyl optionally substituted with a 3-10 membered heterocyclyl, an optionally substituted C_1-6alkylene-3-10 membered heterocyclyl, azetidine optionally substituted with one or more NH₂, or —

(CH₂)_0-4NR¹R².

65. The compound of claim 58, wherein R¹¹ is CH₃, —

CF₃, CHF₂, CH₂F, —

CH₂-piperazine,

76. The compound of claim 63, wherein R¹¹ is NR¹R², R¹ is H, and R² is an optionally substituted —

C_1-4alkyl or an optionally substituted 3-8 membered heterocyclyl.

77. The compound of claim 76, wherein R² is azetidine,

83. The compound of claim 1, wherein R¹¹ is —

C(O)NR¹R², —

NR¹C(O)R⁵, —

N((CH₂)_0-4—

NR¹R²)₂, —

NR¹—

CH—

[(CH₂)_0-4—

NR^1aR^2a]₂, —

NH(CH₂)_1-4—

NR¹R², is —

NR¹(CH₂)_0-4C(═

NR²)R⁵, —

S(CH₂)_0-4C(═

NR¹)R⁵, —

S(CH₂)_0-4-3-10 membered heterocyclyl, —

S(O)₂NR¹R², —

S(CH₂)_0-4—

NR¹R², —

SR³, —

S(CH₂)_1-4-3-10 membered heterocyclyl, —

S(CH₂)_1-4—

R³, —

S(CH₂)_0-4-5-10 membered heteroaryl-NH₂, —

OR³, —

O(CH₂)_0-4—

NR¹R², or —

O(CH₂)₂NH₂.

84. The compound of claim 1, wherein R¹¹ is —

CONH₂, —

NHCOH, —

NHCOCH₃, —

N((CH₂)₂—

NH₂)₂, —

NHCH(CH₂—

NH₂)₂, —

NH(CH₂)₂—

NH-azetidine, —

NHC(═

NH)NH₂, —

SCH₂C(═

NH)NH₂, —

S(CH₂)₂-piperazine, —

S(O)₂NH₂, —

S(CH₂)₂NH₂ or —

S(CH₂)₃NH₂, azetidine, piperidine, —

S(CH₂)₂-morpholine, or

113. The compound of claim 1, wherein R⁷ is selected from the group consisting of —

H, —

OH, —

C_1-4alkyl, —

O—

C_1-4alkyl, —

S—

C_1-4alkyl, halogen, —

CF₃, and cyano.

114. The compound of claim 1, wherein R⁷ is selected from the group consisting of H, F, Cl, Me, —

CF₃, SMe, —

S(O)Me, and —

OMe.

120. The compound of claim 1, wherein R⁷ is present 1 to 3 times and each R⁷ is triazole.

121. The compound of claim 1, wherein:

R⁷ is present 1 to 3 times and each R⁷ is independently —

(CH₂)_m—

Y′

—

(CH₂)_pM′

;

m and p are independently 0 to 3;

Y′

is selected from the group consisting of —

S—

, —

O— and

—

NR¹—

;

M′

is selected from the group consisting of NR¹R², —

SO₃R³, —

CN, —

C(O)NR¹R²;

CF₃, —

C_1-4 alkyl optionally substituted with 1-2 substituents selected from the group consisting, —

OR³, —

NR¹R², halogen, —

C(O)NR¹R², and —

NR¹C(O)R⁵;

C_3-10 cycloalkyl optionally substituted with 1-2 substituents selected from the group consisting of C_1-4 alkyl, —

OR³, —

NR¹R², halogen, —

C(O)NR¹R², and —

NR¹C(O)R⁵;

C_6-10 aryl optionally substituted with 1-2 substituents selected from the group consisting of C_1-4 alkyl, —

OR³, —

NR¹R², halogen, —

C(O)NR¹R², and —

NR¹C(O)R⁵;

5 to 10 membered heteroaryl optionally substituted with 1-2 substituents selected from the group consisting of C_1-4 alkyl, —

OR³, —

NR¹R², halogen, —

C(O)NR¹R², and —

NR¹C(O)R⁵; and

4 to 10 membered heterocyclyl optionally substituted with 1-2 substituents selected from the group consisting of C_1-4 alkyl, —

OR³, —

NR¹R², halogen, —

C(O)NR¹R², and —

NR¹C(O)R⁵.

124. The compound of claim 121, wherein Y′

is O or NH; and

p is 0, 1, or 2.

127. The compound of claim 121, wherein M′

is cyclopropyl, —

SO₃CH₃, SCH₃, —

NH₂, CN, CHF₂, (CH₂)₂F, (CH₂)₂OCH₃, CH₃, CH₂CH₃, CH(CH₃)₂CH₂CH(CH₃)₂,

128. The compound of claim 121, wherein M′

is C_1-4 alkyl optionally substituted with 0-2 substituents selected from the group consisting, —

OR³, —

NR¹R², halogen, —

C(O)NR¹R², and —

NR¹C(O)R⁵;

C(O)NR¹R² wherein R¹ is H and R¹ is azetidine;

a 5 to 10 membered heteroaryl;

or a thiadiazole.

137. The compound of claim 1, wherein

R⁷ is present 1 to 3 times and each R⁷ is independently selected from the group consisting of —

OH, halogen, —

CF₃, C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆ heteroalkyl, C₃-C₇ carbocyclyl, 5-10 membered heterocyclyl, aryl, 5-10 membered heteroaryl, cyano, C₁-C₆ alkoxy(C₁-C₆)alkyl, aryloxy, sulfhydryl (mercapto), and —

(CH₂)_m—

Y′

—

(CH₂)_pM′

;

m and p are independently 0 to 3;

Y′

is selected from the group consisting of —

S—

, —

S(O)—

, —

S(O)₂—

, —

O—

, —

CR⁵R⁶—

, and —

NR¹—

;

M′

is selected from the group consisting of —

C(O)NR¹R²;

—

C(O)NR¹OR³;

—

NR¹C(O)R⁵;

—

NR¹C(O)NR²R^1a;

—

NR¹C(O)OR³;

—

NR¹S(O)₂R³;

—

NR¹S(O)₂NR²R^1a;

—

C(═

NR¹)R⁵;

—

C(═

NR¹)NR²R^1a;

NR¹CR⁵(═

NR²);

—

NR¹C(═

NR²)NR^1aR^2a;

C_1-4 alkyl optionally substituted with 0-2 substituents selected from the group consisting, —

OR³, —

NR¹R², halogen, —

C(O)NR¹R², and —

NR¹C(O)R⁵;

C_3-10 cycloalkyl optionally substituted with 0-2 substituents selected from the group consisting of C_1-4 alkyl, —

OR³, —

NR¹R², halogen, —

C(O)NR¹R², and —

NR¹C(O)R⁵;

C_6-10 aryl optionally substituted with 0-2 substituents selected from the group consisting of C_1-4 alkyl, —

OR³, —

NR¹R², halogen, —

C(O)NR¹R², and —

NR¹C(O)R⁵;

5 to 10 membered heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of C_1-4 alkyl, —

OR³, —

NR¹R², halogen, —

C(O)NR¹R², and —

NR¹C(O)R⁵; and

4 to 10 membered heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of C_1-4 alkyl, —

OR³, —

NR¹R², halogen, —

C(O)NR¹R², and —

NR¹C(O)R⁵; and

with the proviso that the compound does not have the structure selected from the group consisting of

138. The compound of claim 137, wherein each R⁷ is independently selected from —

OH, —

O—

C_1-4alkyl, —

S—

C_1-4alkyl, —

S(O)—

C_1-4alkyl, and halogen; and

wherein R is —

CR⁵R⁶OC(O)C_1-9alkyl or —

CR⁵R⁶OC(O)OC_1-9alkyl.

141. The compound of claim 137, wherein R¹ is H and R² is H.

142. The compound of claim 1, having the structure selected from the group consisting of:

148. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient.

151. The pharmaceutical composition of claim 148, further comprising an additional medicament, wherein the additional medicament is selected from an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent.

153. The composition of claim 151, wherein the additional medicament is a β

-lactam antibacterial agent selected from Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Tebipenem, Apapenem, Panipenem, Aztreonam, Tigemonam, BAL30072, SYN 2416, or Carumonam.

157. A method of treating a bacterial infection, comprising administering to a subject in need thereof, a compound of claim 1.

158. The method of claim 157, further comprising administering to the subject an additional medicament, wherein the additional medicament is selected from an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent.

160. The method of claim 157, wherein the additional medicament is a β

-lactam antibacterial agent selected from Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Tebipenem, Apapenem, Panipenem, Aztreonam, Tigemonam BAL30072 SYN 2416;

or Carumonam.

7. (canceled)

9. (canceled)

11. (canceled)

15. (canceled)

17. (canceled)

20-24. -24. (canceled)

26. (canceled)

27. (canceled)

29. (canceled)

31. (canceled)

32. (canceled)

33. (canceled)

34. (canceled)

36. (canceled)

38. (canceled)

40-44. -44. (canceled)

46-55. -55. (canceled)

57. (canceled)

60. (canceled)

61. (canceled)

64. (canceled)

66-75. -75. (canceled)

78-82. -82. (canceled)

85-112. -112. (canceled)

115-119. -119. (canceled)

122. (canceled)

123. (canceled)

125. (canceled)

126. (canceled)

129-136. -136. (canceled)

139. (canceled)

140. (canceled)

143-147. -147. (canceled)

149. (canceled)

150. (canceled)

152. (canceled)

154. (canceled)

155. (canceled)

156. (canceled)

159. (canceled)

161-171. -171. (canceled)