OA17161A

OA17161A - Heteroaromatic compounds as bruton's tyrosine kinase (BTK) inhibitors

Info

Publication number: OA17161A
Application number: OA1201500010
Authority: OA
Inventors: Joerg Martin Bentzien; Angela Kay Berry; Todd Bosanac; Michael Jason Burke; Darren Todd Disalvo; Joshua Courtney Horan; Shuang Liang; Can Mao; Yue Shen; Fariba Soleymanzadeh; Renee M. Zindell
Original assignee: Boehringer Ingelheim International Gmbh
Priority date: 2012-08-10
Filing date: 2013-08-08
Publication date: 2016-03-28

Abstract

The present invention encompasses compounds of the formula (I)

Description

BACKGROUND OFTHE INVENTION

l.TECHNICAL FIELD

The présent invention re ates to novel compounds which inhibit BTK and their use as médicaments.

2. BACKGROUND INFORMATION nase family of human enzymes play important regulatory rôles in signal transduction processes due to their post-translational roteins via the addition of a phosphate group (Hunier, Cell, 1987

Members of the protein k a multitude of distinct modification of spécifie p

50, 823-829). Bruton’s tyrosine kinase (BTK) is a member of the Tec family of tyrosine kinases and plays a criticd rôle in B cell development, activation and antibody production.

exemplifïed in the X-Iinked

B cells in periphery due to block between pro- and pre-B cells Vels of circulatîng antibodies than normal healthy subjects. The

The contribution of BTK to B cell biology is agammaglobulinemîa (XLA) immunodeficiency in humans (reviewed in Lindvall, Immunol Rev 2005, 20' , 200-215 that display attenuated calcium signaling upon BCR engagement, lack mature stage and hâve lower le outcome of recent clinidal trials with B cell depleting anti-CD20 molécules in diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS) support the hypothesis that B cells offer an important intervention node for controlfing autoimmune disorders (Townsend et al. 2010). inhibition of BTK may demonstrated résistance 1993, Clin Exp Immu

As such, atténuation of B cell activation and prolifération via offer similar therapeutic benefit and is consistent with the of BTK-deficient mice to collagen induced arthritis (Jansson, aol 94, 459-xxx) and experimental autoimmune encephalitis to (Svensson et al, 2002 and Mangla et al 2004). Similarly, the clinical efficacy observed with a neutralizing antibody to the B cell stimulating factor BlyS supports a rôle for B cells in the pathophysiology of systemic lupus erythematosus (SLE) (La Cava 2010). Given the necessity for BTK for the production of autoantibodies, including anti-DNA antibodies, in murine models of SLE (Steinberg et al., 1982; Golding et al., 1983; Scribner et al., 1987; Seldin et al.,1987; Sattert îwaite et al., 1998; Takeshita et al., 1998;Whybum et. al., 2003), BTK inhibi tors may offer therapeutic benefit to SLE patients.

Within myeloid cells, BTK signal transduction is necessary for the stimulated release of inflammatory cytokines such as TNF from stimulated monocytes (Horwood, J Exp Med, 2003, 1603-xxx) and for optimal actin cytoskeletal organization and lacunar bone résorption in isolated osteoclasts (Danks, 2011, J Bone and Minerai Research, 26, 182192). Bone marrow derived mast cells lacking BTK exhibit impaired activation-induced degranulation and cytokine release (ref). Given the rôle of BTK in signal transduction processes across multiple cell types împlicated in the pathogenesis of autoimmune and allergie disorders, inhibiti on of BTK activity may provide clinical benefit in diseases such as RA, MS, SLE, asthma and allergie disorders.

SUMMARY OF THE INVENTION

The invention comprises i novel class of heteroaromatic compounds and methods for making and using the same. These compounds are useful for the treatment of autoimmune and allergie disorders in t rat they exhibit good inhibi tory effect upon BTK.

DETAILED DESCRIPTION O F THE INVENTION

In a first generic embodiment, there is provided a compound of the formula (I)

A ring is:

RiisNfRs^or hydrogen;

Cy is aryl or heteroaryl each is substituted by R2 and optionally substituted by halogen, halo Ci4 alkyl, Cm alkyl and Cm alkoxy;

R2 is chosen from: |

L-Ar, Cm alkyl and Cm alkoxy, each Ar, Cm alkyl and Cm alkoxy are optionally substituted by halogen, halo Cm alkyl, Cm alkyl, R3-S(O)_m-, -CN, -C(O)-N(R3)2 or Cm alkoxy;

L is a tînker chosen from a bond, O, >C(O), -(CH₂)n-, -O-(CH2)_n-, -N(R3)-, -N(R3)-(CH₂)_n, -(CH2)_n-N(R₃)-, -C(O)Jn(R₃)-, -C(O)-N(R3)-(CH2)_a-,-N(R₃)-C(O)-N(R3)-, -N(R₃)-C(O)-, -S(O)_m-N(R3)- and -N(R3)-S(O)_m-, wherein the -CH₂- in each Lcan hâve 1-2 hydrogens replaced by Cm alkyl, sàid Cm alkyl groups can optionally cyclize to form a C3.6 cyctoalkyl ring;

Ar is carbocycte, heterocycyl or heteroaryl;

Xi is a tînker chosen from a bond, -(CH₂)n-;

Y is chosen from C7-C10 spirocycte optionally containing 0-1 ring nitrogen atoms, a nitrogen containing mo io- or bi-cyclic heterocycle, carbocycle, aryl, each substituted by one R4;

1-4;

each n is independently each m is independently 0-2;

each R3 is independendy chosen from hydrogen or Cm alkyl;

each Rj is independently chosen from hydrogen, Cm alkyl, Cm alkoxy, Cm alkylCM alkoxy,

-(CH₂)n-heterocycle and heterocycle each heterocycle optionally substituted by halogen, OH and R₃-S(O)_m-;

each group defined above for Cy, R1-R5, Xi and Y can be where possible partially or fully halogenated;

or a pharmaceutically acceptable sait thereof.

In a further embodiment, there is provided a compound of the formula (I) according to the embodiment herein-above and wherein

A ring is:

or a pharmaceutically acceptable sait thereof.

In a further embodimeni , there is provided a compound of the formula (I) according to any of the embodiments herein-above and wherein

Cy is phenyl, pyridînyl, pyridazinyl, pyrimidinyl or pyrazinyl each is substituted by R₂ and optionally substituted by F, Cl or Cm alkoxy;

R₂ is chosen from:

L-Ar and C1.3 alkoxy, each Ar and C1.3 alkoxy are optionally substituted by F, Cl, Cm alkyl, R₃-S(O)2-, -CN, -C(O)-NH(R₃) and Cm alkoxy;

L is a linker chosen from a bond, O, >C(O), -CH₂-, -O-CH₂-, -NH-, -NH-CH₂-, -CH₂-NH-, -C(O)-NH-CH₂-,-NH-ciü)-NH- and -N(R3)-S(O)_ra-;

Ar is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, indolyl, isoindolyl, benzofuranvl, benzimidazolyl, benzothiazolyl, piperidinyl, piperazinyl or pyrrolidinyl or a pharmaceutically acceptable sait thereof.

In a further embodiment, there is provided a compound of the formula (I) according to any of the embodiments herein-above and wherein

Cy is phenyl or pyridinyl, each is substituted by R2 and optionally substituted by F, Cl or C1.2 alkoxy;

R2 is chosen from:

L-Ar and C1.3 alkoxy, each Ar and C1.3 alkoxy are optionally substituted by F, Cl, Cm alkyl, CH₃-S(O)2-, -CN ,|-C(O)-NH(R3) and C1.2 alkoxy;

L is a linker chosen from a bond, O, >C(O), -CH₂-, -O-CH2-, -NH-, -NH-CH2-, -CH₂-NH-, -C(0)-NH-CH₂-,-NH-CÎ0)-NH- and -N(R₃)-S(O)_m-;

Ar is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, indolyl, isoindolyl, benzofuranyl, benzimidazolyl, benzothiazolyl or piperidinyl or a pharmaceutically acceptable sait thereof.

Cy is phenyl or pyridinyl, each is substituted by R2 and optionally substituted by F, Cl or

Ci-2 alkoxy; R₂ is chosen from:

L-Ar and C1.3 alkoxy, each Ar and C1.3 alkoxy are optionally substituted by F, Cl, C14 alkyl, CH₃-S(O)2-, -CN, -C(O)-NH(CH3) and C^ alkoxy;

L is a linker chosen from a bond, O, >C(O), -CH₂-, -O-CH₂-, -NH-, -NH-CH₂-, -CH₂-NH-, -C(O)-NH-CH₂-,-NH-C(O)-NH- and -N(H)-S(O)₂-;

Ar is phenyl, pyridinyl, penzoxazolyl or piperidinyl or a pharmaceutically acceptable sait thereof.

In a further embodimen :, there is provided a compound of the formula (I) according to any of the embodiments herein-above and wherein Xi is a linker chosen from a bond and -(CH₂)_D-;

Y is chosen from:

a spirocycle chosen from

a heterocycle chosen from pîperidinyl and pyrrolidinyl; and phenyl each heterocycle or phenyl substituted by one R4;

or each R4 is optionally halogenated;

each Rs is independently chosen from hydrogen, Ci.3 alkyl, halo C1.3 alkyl, C1.3 alkylCi.3 alkoxy, -CH2-heterocycle and heterocycle each heterocycle optionally substituted by F, Cl, OH and CH₃-S(O)2- and each heterocycle chosen from pyrrolidinyl, pîperidinyl, morpholinyl and 1,4-oxazepane, or a pharmaceutically acceptable sait thereof.

Xi is a linker chosen from a bond and -(0¾)^

Y is chosen from:

a spirocycle chosen from

a heterocycle chosen from piper idinyl and pyrrolidinyl; and phenyl each heterocycle or phenyl substituted by one R4;

or hydrogen.

each Rj is independently chosen from hydrogen, C4.3 alkyl, -CF3, C].₃ alkytCi.3 alkoxy, CHi-heterocycle and heterocycle each heterocycle optionally substituted by F, Cl, OH and 10 CH₃-S(O)2- and each heterocycle chosen from pyrrolidinyl, piperidinyl and 1,4-oxazepane, or a pharmaceutically acceptable sait thereof.

In a further embodiment, there is provided a compound of the formula (I) according to any 15 of the embodiments herein-above and wherein

»

or a pharmaceutically acceptable sait thereof.

X-Y =

t »

« » »

pharmaceutically acceptable sait thereof.

In a further embodîment, there is provided a compound of the formula (I) according to any of the embodiments herein-above and wherein

A ring is:

thereof.

or a pharmaceutically acceptable sait

A ring is:

to ’** or a pharmaceutically acceptable sait thereof.

A ring is:

or a pharmaceutically acceptable sait thereof.

A ring is:

or a pharmaceutically acceptable sait thereof.

R₂is

LrAr;

L is a linker chosen from a bond, O, and -O-(CH₂)_n-;

nîs 1-3;

Ar is carbocycle or heterocycle;

or a pharmaceutically acceptable sait thereof.

In a further embodiment, there is provided a compound of the formula (I) according to any of the embodiments hereinabove and wherein

Ar is C3.5 cycloalkyl or tetrahydrofuranyl;

n= 1;

or a pharmaceutically acceptable sait thereof.

L-Ar is or or a pharmaceutically acceptable sait thereof.

R₂is:

, -OCH₂CHj, -OCH₂CH₂CHj, -OCHj, -OCF₂ or -OCH₂CF₂;

or a pharmaceutically acceptable sait thereof.

In another embodiment, the invention provides made compounds in Table I which can be made in view of the general schemes, examples and methods known in the art.

Table of compounds and Biological activitv

Exemple	Structure	BTKIC50(nM)	HPLC Method	RT (min)	r
1	A AXyO Z—Z O	2600	A	4.13	401.2
2	? ^NH» ⁰ O b^ o	33	A	4.0S	431.3

3	r-O ΓΥ° nh₂X 0	810	A	4.06	4313
4	ο y—z z x °Λ	-	A	2.56	382.4
5	Q \ss° nh₂ y=^ X 0	-	A	2.59	438.4
6	ΓΓΌ X O	-	A	2.75	405.4

7	α,ρΛ ^ΝΗ» X 0	-	A	2.83	4173
8	ο \'^Ν νη₂ δ-<· ο	-	A	2.61	391.2
9	7^Η» °χ b^ 0	14	A	4.11	415.3
10	η*®' ° ΝΗ ^νηϊ γ⁵^ X 0	•	A	4.14	4943

11	ψΟ ΓΥπ ΝΗ, A 0	5500	A	2.80	494.2
12	α y=o ^NHz Ύ δ-<- ο	-	A	2.67	422.3
13	ο νη, A 0	-	A	236	409.3
14	4^V \'^N νη, 'τ ^οΛο ο	7800	A	2.81	419.4

15	Ό	-	A	2.89	394.4
ΝΗ₂° Ιί	ό ο
	ΝΗ,	θ~->
16	° ιί		580	A	2.77	365.3
		O-C ο
	ΝΗ,	οΧ Çr/
17	⁰ L	£	4800	A	2.60	418.4
		O-r ο
	ΝΗ,
18	° ιί	ϊ	-	A	2.72	371.4
		O-r ο

19	\ b o__Γ nh, X 0	-	A	2.84	433.3
20	o-Q·” xS ^αnh, X O	30	A	3.03	515.2
21	P Γγ^α NH, X 0	98	A	2.85	466.3
22	rO nh, °x b^ O	7.6	A	2.91	447.3

23	_F ρΌ nh₂ ⁰ ο 0	10	A	2.97	435.3
24	<yrO nh, b^ 0	9.4	A	3.02	451.3
25	ÇC nh, ° ir> b^ 0	5.1	A	3.03	527.3

26	F f y-F NH, X o	22	A	3.03	560.3
27	NH nh, y=^ ^0<?ΐΓν X 0	300	A	2.84	4573
28	ρΌ ^nhï y⁵⁵^ °x	35	A	2.85	4293

29	ρΌ νη, V 0	3.2	A	2.83	417.3
30	ρ-Ό ^ΝΗϊ γ⁵^ AS 0	57	A	234	47435
31	Ρ-Ό νη, γ^ AS 6/ 0	80	A	2.86	429.35
32	yO νη, y=^ ⁰ L> A 0	150	A	2.81	429.35

33	P-O ΝΗ₂ Y 0	9.7	A	2.83	41735
34	p-Q νη₂ y=» V* 0	21	A	2.78	394.35
35	P-O NH₂ ⁰ Jl> A oH	0.77	A	2.96	444.3

36	ρΌ νη₂ 0	230	A	2.67	474.3
	Ρ-Ο νη, γ=3
37	Λ	38	A	231	500.3
	Ύ\ ο 1
38	ρ-Ό ^ΝΗ» Λ	13	A	2.84	455.3
	ο

39	P-O nh₂ ⁰ A L V O	290	A	2.65	377.2
40	X) NH, ° L> o	4.9	A	2.89	443.2
41	aO NH, ° A/ X	0.73	A	2.99	456.3
42	P-O NH, \=b °	64	A	2.92	417.4

43	,-Ο ΝΗ, ⁰ \|Γ> ρ	51	A	2.93	429.4
44	Ρ-Ο ^νηϊ ° A/ «ΧΛ V* 0	1	A	2.68	392.4
45	,-Ο ΝΗ, \==^ V	10	A	2.83	431.4
46	ρΌ ΝΗ, ^Ο<Τ/Ν ΗΝ-Χ ΟίΓ 0	1.2	A	2.85	417.4

47	rO NH_â ⁰ ο 0	10	A	2.84	431.4
48	Ρ-Ο ΝΗ₂	90	A	2.97	443.4
49	ρ-Ο νκ, γ=^ ^ο<τΓν ο / αζ 0	180	A	2.96	443.4
50	Ρ--Ο νη, °1γ 0	3	A	2.98	434.3

51	ρΌ ΝΗ₂ Ζν- Vx-C 0	1.7	A	3.00	434.3
52	Ρ-Ο ΝΗ₂ ° 6Ζ 0	18	A	3.02	446.3
53	ρΌ νη₂ y®* ° s^^N «X 0	14	A	3.00	446.3
54	J>O νη₂ ^:C ο	0.73	A	3.00	432.4

55	P-O ^nhî 1	6.6	A	2.93	417.4
56	rO NH_a ô X-	15	A	2.95	429.4
57	P-O NH_a h	3.2	A	2.99	446.3

58	P-O NH, yk	1.1	A	3.01	458.3
59	NIH, yk ^0<Ύ\ W 0	8.9	A	2.75	429.4
60	-Q o=T NH NH, X O	41	A	2.82	473.4

61	ryci °'S^ ^Cl ⁰ JW ^NHi ^οΛο b^ 0	780	A	2.86	548.1
62	jO nh, y^ X 0	93	A	2.97	435.3
63	xx Nn_a ys/ °x b-r 0	660	A	3.08	485.3
64	f=\Js° jJJ ' nh₂ y^ ⁰ V bv 0	6500	A	2.79	495.1

65	rQ ο rS λ° ΝΗ, °χ δ^ 0	330	Β	0.65	495.1
66	XV Γ/ ^FNH, \sss/ X 0	43	A	3.10	469.2
67	ρΟ°' ΝΗ, \ss& °χ b^ ο	38	A	2.95	447.3
68	ρΌ Γ/ ^αΝΗ, ο	41	A	3.08	451.4

69	P-W fz ^Cl NH, \=^ X 0	43	A	3.20	4853
70	X NH_t ^0<tTv X 0	45	A	3.07	4513
71	nh, X 0	14	A	3.04	431.4
72	yX ip X/ X 0	4	A	3.04	431.4

73	rs ^F NH₂ \ss=/ 0 O b^ 0	9.3	A	3.00	435.3
74	rQ fS ^FNH, “O b^ O	-	A	2.89	453.3
75	NH, 0	6600	A	2.91	442.3
76	,-Q rS nh, X 0	61	A	2.92	442.4

77	ρ-Ό νη, °Α> Η,Ν \ V Q	1.9	A	2.72	543.3
78	ρ-Ό νη, Λ α-Χ 0	2.1	A	2.95	472.2
79	Ρ-Ό ΝΗ, Λ 0	6.4	A	3.05	460.2

80	νη, ⁰ jKn A 7.....i 0	0.93	A	3.04	458.4
81	p-O NH, 4=* Ά ? O	0.79	A	2.91	458.3
82	p-O NH, ⁰ jT> Η,Ν^-Χ b	2	A	2.95	472.2
83	x «k Ίζ Vz 'A Il ^w	2.1	A	2.99	484.3

84	t	52	A	3.10	474.2
85	ο Il	300	A	3.11	486.2
86	P-O ^NHi yd h	95	A	3.03	457.4

87	ο Μ-Υ Y ιι	43	A	2.87	469.3
88	ρ-Ό νη, Λ 0	21	A	2.96	443.4
89	ρΌ Nn_t Λ 0	34	A	2.98	455.3
90	,-Ο ΝΗ, ⁰ L>	90	B	035	460.1

91	α-Ο NH, ⁰ A? V	0.79	A	2.94	470.3
92	P-O nh, yG ° A/ 0	0.89	A	2.88	470.3
93	P-O nh, yk ^ο<τίν V O	33	A	2.80	514.3
94	vO NH, yssJ X O	8200	A	2.75	436.3

95	.Τ' ^ΝΗ· X ο	1600	A	2.71	399.3
96	X ΝΗ, X ο	4.8	A	2.95	435.3
97	X ΝΗ, 0	0.8	A	2.93	458.3
98	Ρ-Ο ΝΗ, γ=^ °χ Λ Ο 1	0.7	A	2.69	515.4

99	P-O nh, ° A> A Ï^Q	3.2	A	2.76	557.3
100	9-0 nh, ⁰ JQ >ν \ K	0.8	A	2.63	501.3
101	nh, ° AJ • K □H	9.2	A	2.71	445.4

102	nh, ° H.N V V	2.7	A	2.83	4573
103	X) nh, 7=3 ⁰ x$ H/J \ V	2.8	A	3.13	445.2
104	7 NH, \s3 ⁰ □H	19	A	2.79	422.4
105	Λ NH, ⁰A> H.N Y k	13	A	2.77	410.3

106	A rS NH,	13	A	2.81	422.4
° J Η/ί	II

	NH,	ό
	⁰ ïï
107	II	V	33	A	2.81	422.4
		<? -

	NH,	O
	⁰ li
108	Η/Γ		14	A	2.75	4483
		J -

	NH	O »

109	H,N^Z		24	A	2.86	4363

110	rO	0.87	A	3.09	457.3
n NH, \ ⁰ jd H,NI *	II

	NH,	o
111	⁰ 1 Η/Γ	V	16	A	2.77	410.4
		oH

	NH,	o
	⁰ \|T
112	Η,Ν^	X	6.7	A	2.82	408.4

	NH,	o
	⁰ 1Γ
113	Η,Ν'^'	oK	4.3	A	2.85	420.4

114	ΝΗ₍ Ύ % 0	3.4	A	2.87	4593
115	Ο-ϊ °γ^ Υζ, II	3.5	A	2.82	4623
116	Y ΝΗ, γ=^ °Λ> vr V	12	A	2,78	4503

117	τ-Ο NH, Xs=N <5 0	1.1	A	332	459.2
118	ρΌ NH, \s=N £ o	03	A	3.49	471.2
119	rO NH, \==N O	11	A	3.25	471.3

120	rO NH, \=N ^0<ΊΤΓν 0	33	A	3.29	459.2
121	P^O NH, \s=N ° A> K	0.2	A	3.13	472.2
122	X) nh, ° X> A 0	17	A	2.91	4713
123	J>O NH, y=^* ⁰ A> 'Λ 0	9.1	A	2.88	4593

	Nh	rs
124	(Τ' H/J'	X	10	B	1.73	444.1
		oH
		.r
	NH,	O
125	⁰ J HJ*	X	73	B	0.85	424.0
		7~i 0
		X'
	NH,	O
126	° J	î	28	A	2.98	424.3
		7Ί 0

127	NH, ° JL	a θ o	15	B	0.86	436
		X
		r?
	NH,
	⁰ if	A
128	II h/t		0.9	A	3.02	446.4
		0
		^f\C-f
		fA
	NH,	\==^
	° if	A
129			29	B	0.85	446.1
		O
		Ÿ^F
		r?
	NH,
	(A	fAj
130	X	%	6.4	A	3	434.4
		0

131	νη, ⁰ χ> % O	28	B	0.80	433.9
132	p-O nh, ⁰ A> C\ V^Ny^ O	1.9	B	1.02	4513
133	OH nh, ° Λ7 A K	8.4	A	2.64	368.3
134	A nh, y=^ ⁰ JQ Η.Ν A V	120	B	0.59	438.3

135	νη, A οΗ	26	A	2.83	454.3
136	II	14	B	0.91	466
137	A nh, ° JL> O	1.6	B	0.89	494.1
138	pZ f / NH, yA ⁰ A> X	2.2	B	0.86	440.1

139	F / nh, 1	16	Β	0.56	428.1
140	nh, :λ· Ο-Χ 0	0.9	Β	0,90	436,2
141	II Jt Γ-ζΑο ζ-/'^ζο ^χ	14	Β	0.87	450.0
142	<	29	Β	0.82	438.0

143	^Fx7 F F\ J	37	B	0.85	450.0
NH, ° JL	11
	F F- NH	Ύ$
		T>
144	hX		72	B	0.80	438.1
	^Clx NH,	ό
145	° A	<	33	A	3.17	458.4
		O
	&
	Ό__f Î7 NH,
146	⁰ J	5 y	22	A	2.95	482.4
		7Ί 0

		F. F r^F
		r?
	NH,
	⁰ ïï	A
147	H,rr	i	9.2	B	0.84	432.0
		cf -
		y'
	O,	O
	NH,	F⁵⁵⁷
	⁰ îf	A
148	II H_thl·		3.0	A	3.03	456.3
		J -

	Ί	O
	NH,
149		7	100	B	0.78	480.4
		V
		<f -
		o-Q
		fA
	NH,
	⁰ ιί	A
150	Π	V	0.8	B	0.83	471.2

151	ρΌ νη, 'Λ b	0.7	B	0.78	4713
152	νη, \==/ ° JL?	15	B	0.73	4593
153	νη, γ=/ ⁰ jT>	23	B	0.68	396.1
154	νη, ys=^ ⁰ JL? ' ν	0.6	B	0.71	408.3

155	<( ΝΗ, Χ==^ ⁰ Λ? Λ	7.3	Β	0.69	396.2
156	ΝΗ, y** ⁰ JL? Λ 0	16	Β	0.70	420.4 [M-HJ+
157	ο-4 ΝΗ, Çj ⁰ Λ? ' V	2.0	Β	0.86	434.6
158	ΝΗ, ys=Z J I α ° Λ>	6.3	Β	0.80	442.1

159	NH, \ss/ ^σ Ar	20	B	0.75	430.2
160	Y NH, ys=/ ⁰ A> 0	1.4	B	0.87	462.1
161	a NH, Y	1.1	B	0.87	454.462.8
162	NH, xY °iv a_r	9.2	B	0.91	450.2

163	NH, ys ⁰ Λ ο	4.8	B	0.86	4645
164	νη, yZ °SS ' V	05	B	0.90	476.2
165	_rJ~ nh, yZ ⁰ A? F ^Vny^ 0	15	B	0.89	440.2 [MHJ+443.2
166	ck/ nh, yF Λ	6.6	B	1.06	420.3

167	NH, ⁰ JÎ μ,νΤ'		0.9	B	0.75	422.2
O 7Ί n	Y
	NH,	O
168	⁰ Ji	't		1.2	B	0.84	436.3
		7ί n

or the pharmaceutically acceptable salts thereof.

The présent invention further relates to métabolites, and prodrugs of compounds of the 5 formula (I).

The présent invention further relates to a pharmaceutically acceptable sait of a compound of the formula (I) with inorganic or organic acids or bases.

In another aspect the invention relates to compounds of formula (I) - or the pharmaceutically acceptable salts thereof- as médicaments.

In another aspect the invention relates to compounds of formula (I) - or the pharmaceutically acceptable salts thereof- for use in a method for treatment of a patient.

In another aspect the invention relates to compounds of formula (I) - or the pharmaceutically acceptable salts thereof - for use in the treatment of autoimmune diseases and allergie disorders.

In another aspect the invention relates to the use of compounds of formula (I) - or the pharmaceutically acceptable salts thereof - for preparing a pharmaceutical composition for the treatment of autoimmune diseases and allergie disorders.

In another aspect the invention relates to a method for the treatment of autoimmune diseases and allergie disorders comprising administering a therapeutically effective amount of a compound of formula (I) - or one of the pharmaceutically acceptable salts thereof - to a patient.

In another aspect the invention relates to a pharmaceutical préparation containing as active substance one or more compounds of formula (I)- or the pharmaceutically acceptable salts thereof - optionally in combination with conventional excipients and/or carriers.

Définitions

Terms that are not specifîcally defined here hâve the meanings that are apparent to the skilled man in the light of the overall disclosure and the context as a whole.

As used herein, the following définitions apply, unless stated otherwise:

The use of the prefïx C^y, wherein x and y each represent a natural number, indicates that the chain or ring structure or combination of chain and ring structure as a whole, specified and mentioned in direct association, may consist of a maximum of y and a minimum of x carbon atoms.

Alkyl dénotés monovalent, saturated hydrocarbon chains, which may be présent in both straight-chain (unbranched) and branched form. If an alkyl is substituted, the substitution may take place independently of one another, by mono- or polysubstitution in each case, on ail the hydrogen-carrying carbon atoms.

For example, the term Ci.jalkyl includes for example H₃C-, H₃C-CH₂-, H₃C-CH₂-CH₂-, H₃C-CH(CH₃)-, H₃C-CH₂-CH₂-CH₂-, H₃C-CH₂-CH(CH₃)-, H₃C-CH(CH₃)-CH₂-, h₃cCÎCH₃)2-, H₃C-CH₂-CH₂-CH₂-CH₂-, H₃C-CH₂-CH₂-CH(CH₃)-, H₃C-CH₂-CH(CH₃)-CH₂-, H₃C-CH(CH₃)-CH₂-CH₂-, H₃C-CH₂-C(CH₃)2-, H₃C-C(CH₃)2-CH₂-, H₃C-CH(CH₃)CH(CH₃)- and H₃C-CH₂-CH(CH₂CH₃)-.

Further examples of alkyl are methyl (Me; -CH₃), ethyl (Et; -CH₂CH₃), 1-propyl (n-propyl; π-Pr; -CH₂CH₂CH₃), 2-propyl (z-Pr; wo-propyl; -CH(CH₃)₂), 1-butyl (n-butyl; n-Bu; -CH₂CH₂CH₂CH₃), 2-methyl-l-propyl (iso-butyI; i-Bu; -CH₂CH(CH₃)2), 2-butyl (secbutyl; sec-Bu; -CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (rert-butyl; r-Bu; -C(CH₃)₃), 16t pentyl (π-pentyl; -CH2CH2CH2CH2CH3), 2-pentyl (-CHfCFyCFhCfyCHs), 3-pentyl (-CH(CH₂CH₃)2), 3-methyl-l-butyl («o-pentyl; -CH₂CH₂CH(CH3)2), 2-methyl-2-butyl (-C(CH₃)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH₃)2), 2,2-dimethyl-l-propyl (neo-pentyl; -CH₂C(CH₃)3), 2-methyl-l-butyl (-CH2CH(CH₃)CH₂CH3), 1-hexyl (n-hexyl; -CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH₂CH₃), 3-hexyl (-CH(CH2CH3)(CH2CH₂CH3)), 2-methyl-2-pentyl (-CCCHshCHïCHiCHa), 3-methyl-2pentyl (-CH(CH3)CH(CH3)CH₂CH₃), 4-methyl-2-pentyl (-CH(CH3)CH₂CH(CH₃)2),

3-methyl-3-pentyl (-C(CH3)(CH₂CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH₃)2),

2.3- dimethyl-2-butyl (-C(CH3)2CH(CH₃)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3),

2.3- dimethyl-l-butyl (-CH2CH(CH3)CH(CH₃)CH3), 2,2-dimethyl-l-butyl (-CH2C(CH3)2CH₂CH3), 3,3-dimethyl-l-butyl (-CH₂CH₂C(CH₃)3), 2-methyl-l -pentyl (-CH2CH(CH3)CH2CH₂CH₃), 3-methyl-l -pentyl (-CfyC^CHiC^CHiCHj), 1-heptyl (π-heptyl), 2-methyl-l-hexyl, 3-methyl-l-hexyl, 2,2-dimethyl-l-pentyl,

2.3- dimethyl-l-pentyl, 2,4-dimethyl-l-pentyl, 3,3-dimethyl-l-pentyl, 2,2,3-trimethyl-lbutyl, 3-ethyl-l-pentyl, 1-octyl (π-octyl), 1-nonyl (π-nonyl); 1-decyl (n-decyl) etc.

By the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl etc. without any further définition are meant sa tu rate d hydrocarbon groups with the corresponding number of carbon atoms, wherein ail isomeric forms are included.

The above définition for alkyl also applies if alkyl is a part of another (combined) group such as for example C,._yalkylamino or C,._yalkoxy.

Unlike alkyl, alkenyl consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C-C double bond and a carbon atom can only be part of one C-C double bond. If in an alkyl as hereinbefore defined having at least two carbon atoms, two hydrogen atoms on adjacent carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding alkenyl is formed.

Alkenyl may optionally be présent in the cîs or trans or E or Z orientation with regard to the double bond(s).

Unlike alkyl, alkynyl consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C-C triple bond. If in an alkyl as hereinbefore defined having at least two carbon atoms, two hydrogen atoms in each case at adjacent carbon atoms are formally removed and the free valencies are saturated to form two further bonds, the corresponding alkynyl is formed.

Haloalkyl (haloalkenyl, haloalkynyl) is derived from the previously defined alkyl (alkenyl, 5 alkynyl) by replacing one or more hydrogen atoms of the hydrocarbon chain independently of one another by halogen atoms, which may be identica! or different. If a haloalkyl (haloalkenyl, haloalkynyl) is to be further substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on ail the hydrogen-carrying carbon atoms.

Examples of haloalkyl (haloalkenyl, haloalkynyl) are -CF₃, -CHF2, -CH₂F, -CF₂CF₃, -CHFCF₃, -ch₂cf₃, -CF₂CH₃, -CHFCH₃, -CF₂CF₂CF₃, -CF₂CH₂CH₃, -CF=CF₂, CC1=CH₂, -CBt=CH₂, -OC-CF₃, -CHFCH₂CH₃, -CHFCH₂CF₃ etc.

Halogen relates to fluorine, chlorine, bromine and/or iodine atoms.

Cycloalkyl is made up of the subgroups monocyclic hydrocarbon rings, bicyclic 15 hydrocarbon rings and spiro-hydrocarbon rings. The Systems are saturated. In bicyclic hydrocarbon rings two rings are joined together so that they hâve at least two carbon atoms together.

If a cycloalkyl is to be substituted, the substitutions may take place independently of one 20 another, in the form of mono- or polysubstitutions in each case, on ail the hydrogencarrying carbon atoms. Cycloalkyl itself may be linked as a substituent to the molécule via every suitable position of the ring System.

Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.

Corresponding groups are an example:

Spirocycle is a spiro-hydrocarbon ring one carbon atom (spiroatom) belongs to two rings toge then

Aryl dénotés mono-, bi- or tricyclic carbocycles with at least one aromatic carbocycle. Preferably, it dénotés a monocyclic group with six carbon atoms (phenyl) or a bicyclic group with nine or ten carbon atoms (two six-membered rings or one six-membered ring with a five-membered ring), wherein the second ring may also be aromatic or, however, may also be saturated or partially saturated.

If an aryl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on ail the hydrogencarrying carbon atoms. Aryl itself may be linked as a substituent to the molécule via every suitable position of the ring System.

Examples of aryl are phenyl and naphthyl.

The above définition of aryl also applies if aryl is part of another (combined) group as for example in arylamino, aryloxy or arylalkyl.

Heterocyclyl dénotés ring Systems, which are derived from the previously defined cycloalkyl or spirocycle by replacing one or more of the groups -CH₂- independently of one another in the hydrocarbon rings by the groups -O-, -S- or -NH-, wherein a total of not more than five heteroatoms may be présent, at least one carbon atom may be présent between two oxygen atoms and between two sulphur atoms or between one oxygen and one sulphur atom and the ring as a whole must hâve chemical stability. Heteroatoms may optionally be présent in ail the possible oxidation stages (sulphur -> sulphoxide -SO-, sulphone -SO₂-; nitrogen -> N-oxide).

If a heterocyclyl is substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on ail the hydrogencarrying carbon and/or nitrogen atoms. Heterocyclyl itself may be linked as a substituent to the molécule via every suitable position of the ring System.

Examples of heterocyclyl are tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, or the fotlowing heterocyclic spirocycles

Heteroaryl dénotés monocydic heteroaromatic rings or polycyctic rings with at least one heteroaromatic ring, which compared with the corresponding aryl or cyctoatkyl, instead of one or more carbon atoms, one or more identical or different heteroatoms, selected independently of one another from among nitrogen, sulphur and oxygen, wherein the resulting group must be chemicaHy stable. The prerequisîte for the presence of heteroaryl is a heteroatom and a heteroaromatic System.

If a heteroaryl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on ail the hydrogencarrying carbon and/or nitrogen atoms. Heteroaryl itself may be linked as a substituent to the molécule via every suitable position of the ring System, both carbon and nitrogen.

Examples of heteroaryl are , pyridinyt, pyrîdazinyt, pyrimidinyt, pyrazinyl, benzoxazolyl, indolyl, isoindolyl, benzofuranyl, benzimidazolyl, benzothiazolyl, and the like.

Heteroatoms may optionally be présent in ail the possible oxidation stages (sulphur sulphoxide -SO-, sutphone -SO2-; nitrogen -> N-oxide).

Carbocycles indu de hydrocarbon rings containing from three to twelve carbon atoms. These carbocycles may be either aromatic either aromatic or non-aromatic ring Systems. The non-aromatic ring Systems may be mono- or polyunsaturated. Preferred carbocycles include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyctohexenyl, cycloheptanyl, cycloheptenyl, phenyl, indanyl, indenyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl, decahydronaphthyl, benzocycloheptanyl and benzocydoheptenyl.

Ail cyclic and acyclic Systems defîned in this section hereinabove shall be understood to be optionally partially or fully halogenated where possible and unless otherwise indicated.

Stereochemistry/solvates/hydrates: Unless specifîcally indicated, throughout the spécification and appended daims, a given chemical formula or name shall encompass tautomers and ail stéréo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers, etc.) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoîng forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof. The compounds and salts of the invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, éthanol and the lîke. In general, the solvated forms such as hydrates are considered équivalent to the unsolvated forms for the purposes of the invention.

Salts: The phrase pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of Sound medical judgement, suitable for use in contact with the tissues of human beings and animais without excessive toxicity, irritation, allergie response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.

As used herein pharmaceutically acceptable salts refers to dérivatives of the disclosed compounds wherein the parent compound is modifîed by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, minera! or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.

For example, such salts include acétates, ascorbates, benzenesulphonates, benzoates, besylates, bicarbonates, bitartrates, bromides/hydrobromides, Ca-edetates/edetates, camsylates, carbonates, chlorides/hydrochlorides, citrates, edisylates, ethane disulphonates, estolates esylates, fumarates, gluceptates, gluconates, glutamates, glycolates, glycollylaranîlates, hexylresorcinates, hydrabamines, hydroxymaleates, hydroxynaphthoates, iodides, isothionates, lactates, lactobionates, malates, maleates, mandelates, methanesulphonates, mesylates, methylbromides, methylnitrates, methylsulphates, mucates, napsylates, nitrates, oxalates, pamoates, pantothenates, phenyl acétates, phosphates/diphosphates, polygalacturonates, propionates, salicylates, stéarates, subacetates, succinates, sulphamides, sulphates, tannates, tartrates, teoclates, toluenesulphonates, triethiodides, ammonium, benzathines, chloroprocaines, cholines, diethanolamines, ethylenediamines, meglumines and procaines.

Further pharmaceutically acceptable salts can be formed with cations from metals Iike aluminium, calcium, lithium, magnésium, potassium, sodium, zinc and the Iike (also see Pharmaceutical salts, Birge, S.M. et al., J. Pharm. Sci., (1977), 66,1-19).

The pharmaceutically acceptable salts of the présent invention can be synthesîsed from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a suffïcient amount of the appropriate base or acid in water or in an organic diluent Iike ether, ethyl acetate, éthanol, isopropanol, or acetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the présent invention (e.g. trifluoroacetates), also comprise a part of the invention.

Some abbreviated notations and their structure correspondences are listed below:

In a représentation such as for example the solid line means that the ring System may be attached to the molécule via the carbon atom 1,2 or 3, and is thus équivalent to the following représentation

By a therapeutically effective amount for the purposes of this invention is meant a quantity of substance thaï is capable of obviating symptoms of illness or alleviating these symptoms, or which prolong the survival of a treated patient.

List of abbreviations

Ac	Acetyl
ACN	Acetonitrile
aq	Aqueous
AIT	adenosine triphosphate
Bn	Benzyl
Bu	Butyl
Boc	tert-butyloxycarbonyl
cat	Catalyst
conc	concentrated
d	day(s)
TEC	thin layer chromatography
D1EA	MÆ-d irsopropyle thylamine
DMAP	4-A\jV-dimethy!aminopyridine
DME	1,2- dime thoxye thane
DMF	A\jV-dirnethylformarnide
DMSO	Dime thylsulphoxi de
dppf	l.r-bîs(diphenylphosphino)ferrocene
EDC	1 -Ethy l-3-(3-d ime thyl aminopropyl)carbo di imide
ESI	électron spray ionization
Et	Ethyl
Et₂O	diethyl ether
EtOAc	ethyl acetate
EtOH	Ethanol
h	hour(s)
HATU	0-(7-azabenzotriazol-l-yl)W^AT^r-tetramethyl-uronium hexafluorophosphate

Hep	Heptane
HPLC	high performance liqurd chromatography
i	Iso
LC	liquid chromatography
LiHMDS	lithium bis(trimethylsilyl)amide
sln.	Solution
mCPBA	3-Chloroperoxbenzoic acid
Me	Methyl
MeOH	Methanol
min	Minutes
MPLC	medium pressure liquid chromatography
MS	mass spectrometry
NBS	jV-bromo-succinimide
N1S	jV-iodo-succinimide
NMM	A/-methylmorpholine
NMP	AT-methylpyrrolidone
NP	normal phase
n.a.	not available
PBS	phosphate-buffered saline
Ph	Phenyl
Pr	Propyl
Pyr	Pyridine
rac	Racemîc
Rf(Rr)	rétention factor
RP	reverse d phase
RT	Rétention time (HPLC)
rt	ambient température
TB AF	te trabutyl ammonium fluoride
TBDMS	tert-butyldimethylsilyl

TBME	tert-butylmethylether
TB TU	O-(benzotriazoI-l-yl)-N,N,N’,N'-tetramethyl-uronium tetra fluoroborate
tBu	tert-butyl
TEA	Triethylamine
temp.	Température
tert	Tertiary
Tf	Triflate
TFA	trifluoroacetic acid
THF	Tetrahydrofuran
TMS	Trimethylsilyl
TRIS	tris(hydroxymethyl)-aminomethane
Ts	p-Tosyl
TsOH	p-toluenesulphonic acid
UV	Ultraviolet

Features and advantages of the présent invention will become apparent from the following detailed examples which illustrate the fundamentals of the invention by way of example without restricting its scope:

Préparation of the compounds according to the invention

General Synthetic Methods

Optimum reaction conditions and reaction times may vary depending on the particular reactants used. Unless otherwise specifîed, solvents, températures, pressures and other 10 reaction conditions may be readily selected by one of ordinary skill in the art. Spécifie procedures are provided in the Synthetic Examples section. Intermediates and products may be purifïed by chromatography on silica gel, recrystallization and/or reverse phase HPLC (RHPLC). Discrète enantiomers may be obtained by resolution of racemic products using chiral HPLC. RHPLC purification methods used anywhere from 0-100% acetonitriïe în water containing 0.1% formic acid or 0.1% TFA and used one of the following columns:

a) Waters Sunfire OBD C18 5 μιη 30x150 mm column

b) Waters XBridge OBD C18 5 pm 30x150 mm column

c) Waters ODB C8 5 pm 19x150 mm column.

d) Waters Atlantis ODB C18 5 μπι 19x50 mm column.

e) Waters Atlantis T3 OBD 5 μπι 30x100 mm column

f) Phenomenex Gemini Axia C185 pm 30x100 mm column

HPLC Methods:

Analytical LC/MS Analysis Method A:

Column : Thermo Scientifie, Aquasil Cl8,50 x 2.1 mm, 5 μπι column

Gradient:

Time(min)	0.1% Formic Acid in Water	0.1% Formic Acid in CAN	FJow(ml/min)
0	90	10	03
03	90	10	03
13	1	99	03
25	1	99	03
3.3	90	10	03
4.0	90	10	03

Analytical LC/MS Analysis Method B:

Column; Waters BEH 2.1x50mm C18 1.7 pm column

Gradient:

Time(min)	95%Water/5%ACN(0.05%TFA)	ACN(0.05%TFA)	Flow(ml/min)
0	90	10	0.8
1.19	0	100	0.8
1.7	0	100	0.8

The compounds according to the invention are prepared by the methods of synthesis described hereinafter in which the substituents of the general formulae hâve the meanings given hereinbefore. These methods are intended as an illustration of the invention without restricting its subject matter and the scope of the compounds claimed to these examples. Where the préparation of starting compounds is not described, they are commercially 10 obtainable or may be prepared analogously to known compounds or methods described herein. Substances described in the literature are prepared according to the published methods of synthesis.

Compounds of formula I may be prepared as shown in Scheme la and Ib below.

Scheme la:

AB ^Y

In scheme la, a heterocycle A is treated with a suitable base and reacted with an Xj-Y group containing a leaving group (LG) B to afford the compound of general formula (I).

Scheme lb:
v^x Λ X. + /¾ LG O	- X
Y
	Y
C D	(I)

In scheme Ib, C (where X = O, N, S, or NH₂) is condensed with D to afford the compound of general formula (I).

Synthetic Examples

Method 1

Synthesis of Intermediate 1-1

TsCI.TEA, DMAP

CHgCta

R-1

1-1

A solution of R-1 (5.0 g, 23 mmol) in CH2CI2 is treated with TEA (6.5 mL, 47 mmol) and DMAP (0.57 g, 4.7 mmol). The mixture is stirred for 24 h then concentrated in vacuo.

The residue is dissolved in EtOAc and washed with saturated aqueous ammonium chloride and brine. The organics are collected and volatiles are removed in vacuo. The crude residue is triturated with Et₂O and solid fîltered and collected to afford 1-1 (5.6 g, 65%) mlz 367.9 [M+J.

The following intermediates were prepared in a simîlar manner

Structure	Intermediate	m/z
é'	1-2	396.3 [M+H]
₍x^.,.OTs T	1-3	356.0 [M+H]

Method 2

Synthesis of Intermediate 1*4 and séparation of diastereomers 1-5 and 1-6.

To a solution of PPhjCHjBr (578 g, 1,62 mol) in THF (33 L) is added a solution of nBuLi (600 mL, 13 mol) at -78°C under N₂. The mixture is stirred at 0°C for 1 h then R-2 (200 g, 1.08 mol) in THF (2.0 L) is added to the reaction mixture at 0°C. The mixture is 5 allowed to warm to ambient température, stirred for 1 h, then poured into H₂O and extracted with EtOAc. The organic layers are washed with brine, dried with Na₂SO4, concentrated and purified by flash chromatography (SÎO₂, Hep to 25%EtOAc in Hep) to give compound R-3 (70 g, 36%).

to To a solution of R-3 (20 g, 109 mmol) in Et₂O (150 mL) is added Zn-Cu (56.2 g, 436 mmol) at 10°C under N₂. Trichloroacetyl chloride (39.7 g, 218 mmol) in DME (150 mL) is added. The mixture is allowed to warm to ambient température and stirred for 2 days. The mixture is treated with aqueous NaHCOj and extracted with EtOAc. The organic layers are washed with brine, dried with Na₂SO4, concentrated and purified by flash chromatography (SiO₂, Hep to 25%EtOAc in Hep) to give R-4 (11 g, 34%).

To a solution of R-4 (353 g, 121 mmol) in saturated NH4CI (64.7 g, 1.21 mol) in MeOH (400 mL) is added Zn (79.1 g, 1.21 mol). The mixture is stirred at ambient température for

h. The mixture is treated with H2O and extracted with EtOAc. The organic layers are washed with brine, dried with Na2SO4, concentrated and purified by flash chromatography (SiO₂, Hep to 25%EtOAc in Hep) to afford R-5 (19 g, 69%).

To the mixture of R-5 (19 g, 84.3 mmol) in THF (200 mL) is added NaBFLj (12.8 g, 337.2 mmol) at 0°C and then stirred at ambient température for 6 h. The mixture is treated with MeOH and H2O, then extracted with EtOAc. The organic layers are washed with brine, dried with Na2SÛ4, concentrated and purified by flash chromatography (SiO₂, Hep to 50%EtOAc in Hep) to yield R-6 (12 g, 63%).

To the mixture of R-6 (22 g, 96.8 mmol) and pyridine (23.2 g, 290.4 mmol) in CH2CI2 (300 mL) is added TsCI (27.7 g, 145.2 mmol) at 0 °C and then stirred at ambient température ovemight. The mixture is treated with H₂O and extracted with EtOAc. The organic layers are washed with brine, dried with Na₂SO4, concentrated and purified by flash chromatography (SÎO2, Hep to 40%EtOAc in Hep) to give 1-4 (26.6 g, 72%) mfz

382.2 [M+H]. 1-4 is separated by flash chromatography (SÎO₂, Hep to 40%EtOAc in Hep) to give diastereomers 1-5 (m/z 382.2 [M+H]) and 1-6 (m/z 382.2 [M+H]).

Method 3

Synthesls of Intermediate 1-8

To a solution of R-7 (15.0 g, 97 mmol) in CH2I2 (350 mL) is added isoamyl nitrite (58.7 g, 580 mmol). The solution is stirred for 15 min at ambient température then heated at 70° C for 2 h. The mixture is cooled to ambient température then partitioned between EtOAc and aqueous sodium bisulfite. The organics are collected, dried over MgSQi, filtered, and concentrated in vacuo. The crude is purified by flash chromatography (S1O2, Hep to 50%EtOAc in Hep) to give the 1-7 (13.1 g, 51%) m/z 266.8 [M+H].

A solution of 1-7 (2.0 g, 73 mmol), 4-phenoxyphenylboronic acid (2.0 g, 9.3 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) dichloropalladium(II) (15 g, 2.1 mmol) in DMF (20 mL) and 2M aqueous CS2CO3 (10 mL) is heated at 120° C for 2h. The mixture is cooled to ambient température then partitioned between EtOAc and aqueous NH4CI. The organics are collected, dried over MgSÜ4, filtered, and concentrated in vacuo. The crude is purified by flash chromatography (S1O2, 10-30% EtOAc in Hep) to give 1-8 (1.6 g, 69%). m/z 309.1 [M+H]

Method 4

Synthesis of Intermediate 1-9

R-8

dlmethylsutfate, hydrazine TEA, THF

k9

To malonitrile (735 g, 114 mmol) in THF (200 mL) at 0° C is added sodium hydride (60%dispersion in minerai oil, 437 g, 114 mmol) slowly under a stream of nitrogen. After 10 min R-8 (27 g, 115 mmol) is added and the ice bath removed. The mixture is stirred at ambient température for 13h then dimethylsulfate is added then heated at reflux for 2 h. The mixture is cooled to ambient température then triethylamine and hydrazine are added.

The mixture is heated at reflux for 2 h then concentrated in vacuo, diluted with water, and extracted with 10%MeOH in EtOAc. The organics are collected, dried over MgSOj, fîltered and concentrated. The crude is purified by flash chromatography (S1O2, 0-100% EtOAc in Hep) to afford 1-9 (5.7 g, 18%). mlz 2775 [M+H]

Method 5

Synthesis of Intermedlate 1-10

KCN

DMSO

To a solution of 1-1 (200 mg, 054 mmol) in DMSO (25 mL) was added KCN (71 mg, 1.1 mmol). The mixture was heated at 100° C for 18 h then cooled to ambient température and partitioned between EtOAc and water. The organics were collected, dried over MgSOj, fîltered and concentrated in vacuo to afford 1-10 (quant, 120 mg). mlz 223.1 [M+H]

The following intermediates were prepared in a similar manner

Structure

Intermedlate

mlz

N è 0 K	1-11	181.0 [M-tBu]
N X	1-12	211.1 [M+H]
Γ y
é	1-13	195.4 [M-tBu]
X v

Method 6

Synthesis of Intermediate 1-14

N DMF N

no H4

To a solution of 1-10 (250 mg, 1.1 mmol) in DMF (2 mL) is added 20% (w/w) aqueous (NHf^S (2 mL, 5.9 mmol). The mixture is stirred at ambient température for 17 h then diluted with water. The resulting whîte solid is fîltered and collected to give 1*14 (160 mg, 55%). m!z 257.0 [M+H]

The following intermediates were prepared in a similar manner

Structure	Intermediate	mlz
H₂NyS
Q ^VNy° °K	1*15	271.1 [M+H]
h₂n^s O X	1-16	189.0 [M-tBu]
h₂n^s
	1-17	245.0 [M+H]

ΎΓ F

1-18

285.1 [M+H]

Method 7

Synthesis of Intermediate 1-19

1-13 aq NH_aOH

EtOH

1-19

A solution of 1-13 (422 mg, 1.69 mmol) in EtOH (8.4 mL) is treated with 50% (w/w) aqueous hydroxylamine (1.1 mL, 16.9 mmol). The solution is heated at 70® C for 2 h then volatiles are removed in vacuo to afford 1-19 (478 mg, quant) mlz 284.1 [M+H].

The following intermediates were prepared in similar manner

Structure

Intermediate

mlz

Method 8

Synthesis of Intermediate 1-21

To a solution of 1-8 (200 mg, 0.65 mmol) and CS2CO3 (423 mg, 1.30 mmol) in DMF (3 mL) is added 1-1 (262 mg, 0.71 mmol). The mixture is heated at 60° C for 18 h then concentrated în vacuo. The residue is purified by flash chromatography (S1O2, Hep to 50%EtOAc in Hep) to give 1-21 (217 mg, 66%) m!z 504.2 [M+H].

The following intermediates were prepared in similar fashion:

Structure

Intermediate

m/z

- - o. A Ύ	1-22	492.2 [M+H]
0 /° \ / Y Y=o λ	1-23	518.2 [M+H]
χ-ο __ /° \ / 0-\ O 8 Vo Y	1-24	518.2 [M+H]

__ /° \ 7 0—\ / 0 Φ o'^o

1-25

NA

Method 9

Synthesis of Intermediate 1-26

To a solution of 1-6 (800 mg, 2.6 mmol) in THF (40 mL) is added R-8 (650 mg, 3.0 mmol), tri-n-octyl phosphine (3.0 g, 8.0 mmol), and ADDP (1,1*(azodicarbonyl)dipiperidine) (2.1 g, 8.2 mmol). The mixture is stirred for 48 h then 10 concentrated in vacuo. The residue is partitioned between saturated aqueous NH4CI and

EtOAc. The organics are washed with brine, dried over NaîSO^, filtered, and concentrated in vacuo. The crude is purified by flash chromatography (S1O2, Hep to 30%EtOAc in Hep) to give 1-24 (1.1g, 84%) mlz 506.1 (M+H).

The following intermediates are prepared in similar fashîon:

Structure	Intermediate	m/z
___ /0 \ / O X V-n^o	I-2S	NA
__ /° \ / ^x° \ / H N l	1-26	NA
1 HN^O °r

O^\ / O	1-27	417.9 [M+H]
χΧ __ /° \ 7 o-\ / Q	1-28	NA
Ύ

Method 10

Synthesis of Intermediate 1-30

A solution of 1-21 (260 mg, 0.52 mmol) in 1:1 dioxane/water (8 mL) is treated with LiOH (120 mg, 5.0 mmol). The mixture is heated at reflux for 2 h then volatiles are removed in vacuo. The residue is acidified to pH = 4 with 2M aqueous HCl, extracted with EtOAc, washed with brine, dried over Na₂SO4, filtered, and concentrated in vacuo. The residue is dissolved in DMF (4 mL) and treated with pyridine (80 uL, 1.0 mmol) and Boc anhydride (80 mg, 1.0 mmol). The solution is stirred for 10 min then ammonium bicarbonate (95 mg,

1.2 mmol) is added. The mixture is stirred for 16 h then volatiles are removed in vacuo. The residue is partitioned between EtOAc and saturated aqueous ΝΗ,Ο. The organics are washed with brine, dried over Na₂SO4, filtered, and concentrated in vacuo. The residue is to purified by flash chromatography (SiO₂, 20-80%EtOAc in Hep, then 20%MeOH in

CH2CI2) to give 1-29 (180 mg, 75%) mfz 475.0 [M+H].

To a stirred solution of 1-29 (180 mg, 0.38 mmol) in CH₂CI₂ (3 mL) is added TFA (2 mL). The solution is stirred at ambient température for 3 h then volatiles are removed in vacuo.

The residue is partitioned between saturated aqueous NaHCOj and EtOAc. The organics are collected, dried over Na₂SO4, filtered, and concentrated in vacuo to afford 1-30 (130 mg, 92%) m/z 375.0 [M+H].

The following intermediates were prepared in similar fashion:

Structure	Intermediate	m!z
^Ha^N\ / O A	1-31

H_aN—/ O	1-35
hO η₂ν-ζ^ O N <Ÿ	1-36
n. s NH_a	1-37
Χ) /° \ / H_aN~\ O Ç>-	1-38

Method 11

Synthesls of Intermediate 1*41

To a solution of R-9 (5.00 g, 23.6 mmol) in THF (50 mL) is added a 60% dispersion of sodium hydride in minerai oil (1.41 g, 35.1 mmol). The mixture is stirred for 5 min at ambient température then diethyl carbonate (5.7 mL, 47.4 mmol). The reaction is stirred for 30 min at ambient température then heated at reflux for 2 h. The mixture is cooled to ambient température then partitioned between saturated aqueous NH4CI and EtOAc. The organics are collected and concentrated in vacuo to afford a residue that is purified by flash chromatography (SiO₂, Hep to 70%EtOAc in Hep) to give 1-40 (6.2 g, 93%) m!z 285.1 [M+HJ.

To a cold (0° C) solution of 1-40 (5.2 g, 18.3 mmol) in CH₂C1₂ (46 mL) is added SO₂Ci₂(13 mL, 18.3 mmol). The mixture is allowed to warm to ambient température and stirred for 30 min then treated with water, extracted with CH₂C1₂, dried over Na2SO₄, filtered, and concentrated in vacuo to afford 1*41 (quant) m/z 318.9 [M+H].

Method 12

Synthesis of Intermediate 1*43

1-41, Pyr, /-PrOH

1-19

M2

M3

A solution of 1*15 (400 mg, 1.48 mmol) and 1-41 (943 mg, 2.96 mmol) in i-PrOH (15 mL) is treated with pyridine (0.36 mL, 4.44 mmol). The mixture is heated at 60° C for 3 days then volatiles are removed in vacuo. The residue is purified by flash chromatography (SiO₂, Hep to 40%EtOAc in Hep) to give 1-42 (240 mg, 30%) m/z535.2 [M+H].

A solution of 1-42 (240 mg, 0.45 mmol) in MeOH (3 mL), THF (1 mL), and 5M aqueous NaOH (0.5 mL) is heated at 60° C for 3 h. The mixture is cooled to ambient température then acidifîed to pH=l with 6M aqueous HCl. The mixture is extracted with CH2CI2 then filtered through a phase separator® then volatiles are removed in vacuo. The residue is dîssolved in DMF (2 mL) and treated with pyridine (324 mg, 4.1 mmol), Boc anhydride (327 mg, 0.45 mmol), followed by ammonium bicarbonate (215 mg, 2.72 mmol). The mixture is stirred for 3 h then volatiles are removed in vacuo to afford a residue that is purified by flash chromatography (SiO₂, CH2CI2 to 5%MeOH in CH2CI2). The purified 9t materiat is dissolved in CH2O2 (5 mL) and treated with 4.0M HCl in dioxane (1.1 mL). The mixture is stirred for 1 h then volatiles are removed in vacuo to afford a residue that is purified by flash chromatography (S1O2, CH2CI2 to 20%MeOH in CH2CI2 containing 25%TEA) to give 1-43 (134 mg, 73%) mtz 405.9 [M+H].

The following compounds are made in similar fashion:

Structure	Intermediate	m/z
=/^HÏ >=/ SyN Qh	1-44	380.8 [M+H]
\ 7 o=\ / NH	1-45	380.4 [M+H]

NH,

1-46

NA

Method 13

Synthesis of Intermediate 1-46

To a solution of 1*14 (160 mg, 0.62 mmol) and 1-41 (298 mg, 0.94 mmol) in i-PrOH (6.2 mL) is added pyridine (0.15 mL, 1.9 mmol). The solution is heated at 70° C for 24h then volatiles are removed in vacuo. The crude is purified by flash chromatography (SiO₂, Hep 10 to 40%EtOAc in Hep) to give 1-46 (144 mg, 44%) m/z 521.2 [M+H].

A solution of 1-46 (144 mg, 0.28 mmol) in MeOH (2 mL) and 3M aqueous NaOH (2 mL) is heated at 65° C for 3 h then cooled to ambient température. The solid is filtered, collected, and dried then dissolved in DMF (2 mL) and treated with TBTU (71 mg, 0.22 mmol). The mixture is stirred for 15 min then treated with 7M ammonia in MeOH (7 mL). The mixture is stirred for 20 min then volatiles are removed in vacuo. The residue is partitioned between water and EtOAc and organics are collected and concentrated. The 5 crude is purified by flash chromatography (Hep to EtOAc). The resulting compound is dissolved in CH2CI2 (2 mL) and treated with TFA (1 mL). The reaction mixture is stirred for 2 h then volatiles are removed in vacuo. The crude is partitioned between CH2CI2 and 10% (w/w) aqueous Na₂CO₃ and CH2CI2. The organics are collected and fîltered through a phase separator® to afford after removal of the volatiles 1-47 (58 mg, 53%) m/z 392.1 10 [M+H].

Method 14

Synthesis of Intermedlate 1-51

A solution of 1-20 (500 mg, 2.1 mmol) and methyl propriolate (0.35 mL, 4.1 mmol) in

MeOH (10 mL) is heated at 65° C for 4 h. The mixture is concentrated in vacuo then dissolved in diphenyl ether (2 mL) and heated at 200° C for 1 h. The mixture is cooled to ambient température then purified by flash chromatography (S1O2, Hep to EtOAc) to give 1-48 (317 mg, 50%) m/z 310.2 [M+H].

To a solution of 1-48 (317 mg, 1.0 mmol) and p-TsOH Pyr (461 mg, 2.1 mmol) in CH2CI2 (5 mL) is added NIS (461 mg, 2.1 mmol). The mixture is stirred in the dark at ambient température for 24 h. The mixture is treated with saturated aqueous NajSOj then filtered through a phase separator. The organics are collected and concentrated in vacuo to afford a residue thaï is purified by flash chromatography (S1O2, Hep to 80%EtOAc in Hep) to afford 1-49 (339 mg, 76%) m/z 436.0 [M+H].

A mixture of 1-49 (339 mg, 0.78 mmol), 4-phenoxylphenylboronîc acid (333 mg, 1.56 mmol), and tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.078 mmol), and K3PO4 (827 mg, 3.89 mmol) in dioxane (4 mL) is heated at 100° C in the microwave for 45 min. The mixture is cooled and concentrated in vacuo to afford a residue that is purified by flash chromatography (S1O2, Hep to 80%EtOAc in Hep) to afford 1-50 (302 mg, 81%) m/z 478.2 [M+H].

A solution of 1-50 (372 mg, 0.78 mmol) in MeOH (15 mL), THF (1 mL), and 3M aqueous NaOH (3 mL) is heated at ambient température for 20 h then acidified to pH=5 with concentrated aqueous HCl. The volatiles are removed in vacuo and residue triturated with a mixture of CH2CI2 and MTBE. The solid is filtered, collected, and dried. The solid is dissolved in DMF (2 mL) and treated with pyridine (0.1 mL, 1.2 mmol), Boc anhydride (69 mg, 0.87 mmol), followed by ammonium bicarbonate (96 mg, 1.2 mmol). The mixture is stirred for 16 h then partitioned between water and CH2CI2. The mixture is filtered through a phase separator® and organics are concentrated in vacuo to afford a residue that is purified by flash chromatography (S1O2, CH2CI2 to 5%MeOH in CH2CI2)· The purified material is dissolved in CH2CI2 (2 mL) and treated with 4.0M HCl in dioxane (4 mL). The mixture is stirred for 2 h then volatiles are removed in vacuo to afford a residue that is purified by trituration with MTBE:EtOAc to give 1-51 (75 mg, 22%) mlz 393.1 [M+H].

The following intermediate is prepared in sîmilar fashion:

Structure	Intermediate	mlz
nA	1-52	403.2 [M+H]
St

Method 15

Synthesis of Intermediate 1-54

kS3

To a solution of 1-9 (1.50 g, 5.4 mmol) in DMF (20 mL) is added sodium hydride (60%dispersion in minerai oil, 0.26 g, 65 mmol). The mixture is stirred for 5 min then I-l (2.39 g, 65 mmol) is added. The mixture is heated at 70 ⁰ C for 18 h then cooled to ambient température. The mixture is partitioned between EtOAc and water then organics are collected, dried over Na₂SO4, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (SiO₂, Hep to 70%EtOAc in Hep) to afford 1-53 (1.2 g, 5 47%) m/z 472.2 [M+H].

A solution of 1-53 (1.00 g, 2.2 mmol) in AcOH (5 mL) and Concentrated aqueous HCl (1 mL) is heated at 90° C for 10 h. The mixture is cooled to ambient température then poured into ice. The mixture is basified to pH 9-10 by addition of ammonium hydroxide then 10 extracted with EtOAc, washed with brine, dried over Na₂SO4, filtered, and concentrated in vacuo. The residue is purified by RHPLC to afford 1-54 (0.39 g, 48%) m/z 390.1 [M+H].

The following intermediates are prepared in similar fashion:

Structure	Intermediate	m/z
Y* O tyr-O Oh	1-54	378.1 [M+H]
Y² CJ H Kl N'	1-55	418.2 [M+H]

=Z^Hï >=/ ^nh₂	1-56
aO NH, Ç V) Si⁷	1-57	404.1 [M+H]
9 cX-OCr O £	1-58	404.1 [M+H]

Method 16

Synthesis of Example 9

To a solution of 1-7 (2.00 g, 73 mmol) in DMF (20 mL) is added CS2CO3 (4.9 g, 15 mmol) and 1-3 (4.0 g, 11 mmol). The reaction mixture is heated at 60° C for 24 h then cooled to ambient température. The mixture is partitioned between EtOAc and water. The organics 5 are collected, washed with water, dried over MgSO₄, filtered, and concentrated in vacuo.

The crude is purifïed by flash chromatography (SiO₂, Hep to 30%EtOAc in Hep) to afford 1-59 (2.10 g, 62%) mtz 445.0 [M+H].

To a solution of 1-59 (7.00 g, 15.6 mmol) in 1:1 dioxane:water (50 mL) is added LiOH 10 (3.00 g, 125 mmol). The reaction mixture was heated at reflux for 2h then volatiles are removed in vacuo. The residue is acidified with aqueous 2 N HCl to pH - 4 then diluted with EtOAc, washed with brine, dried over Na2SO₄, filtered, and concentrated in vacuo.

The residue is dissolved in DMF (30 mL) and treated with Boc anhydride (2.22 g, 28 mmol) followed by ammonium bicarbonate (2.21 g, 28 mmol) and pyridine (2.2 mL, 28 15 mmol). The mixture is stirred for 16 h then volatiles are removed in vacuo. The residue is partitioned between EtOAc and saturated aqueous NH4CI then organics are collected, washed with brine, dried over Na₂SO4, filtered, and concentrated in vacuo. The crude is purified by flash chromatography (SiO₂, 20-80%EtOAc in Hep, then 20%MeOH in CH₂C1₂) to afford 1-60 (3.8 g, 61%) m/z 421.0 [M+H]

To a solution of 4-benzylphenylboronic acid pînacol ester (47 mg, 0.16 mmol) in DME (1 mL) îs added a solution of 1-19 (45 mg, 0.11 mmol) in DME (1 mL). To thîs solution is added aqueous 1 M K₂CO₃ (1 mL) and SiliaCat DPP-Pd (50 mg, 0.01 mmol). The mixture is heated at 100° C for 16 h then concentrated in vacuo. The crude was purified by RHPLC to afford a residue thaï is dissolved in DCE and treated with 4.0M HCI in dioxane (05 mL). The mixture is stirred for 16 h then volatiles are removed in vacuo. To the residue is added a solution of acrylic acid (7.7 mg, 0.11 mmol), EDC (23 mg, 0.12 mmol), and DIEA (35 uL, 0.20 mmol) in DMA (0.8 mL). The reaction mixture is stirred for 4 h then volatiles were removed in vacuo to afford a residue that was purified by RHPLC to afford example 9 (12 mg, 26%).

The following compounds were préparé d in a similar manner:

Examples 1-8,10-27,94-96

Method 17

Synthesis of Example 28

100

Ex 28

To a solution of 1-30 (75 mg, 0.20 mmol) in DMF (2 mL) is added D1EA (0.3 mL), TBTU (96 mg, 0.30 mmol), and acrylic acid (22 mg, 0.30 mmol). The mixture is stirred for 12 h at ambient température then treated with water. The mixture is extracted with EtOAc, 5 dried over Na₂SC>4, filtered, and concentrated in vacuo. The crude is purified by flash chromatography (30 to 90%EtOAc in Hep) to give example 28 (36 mg, 42%).

The following compounds are prepared in stmilar fashion:

Examples 29,33,39,42,45,47,55,88

Method 18

Synthesis of Example 38

101

To a solution of 1-32 (70 mg, 0.18 mmol) in DMF (3 mL) is added DIEA (1 mL), TBTU (116 mg, 0.36 mmol), and R-10 (17 mg, 0.20 mmol). The mixture is stirred for 12 h at ambient température then treated with water. The mixture is extracted with EtOAc, dried 5 over NazSOi, fïltered, and concentrated in vacuo. The crude is purified by RHPLC to give example 38 (38 mg, 46%).

The following compounds are prepared in similar fashion:

Examples 31,32,43,48,49,56

Method 19

Synthesls of Example 37

102

To a solution of 1-32 (25 mg, 0.064 mmol) in DMF (2 mL) is added DIEA (0.4 mL), TBTU (32 mg, 0.080 mmol), and R-ll (10 mg, 0.080 mmol). The mixture is stirred for 12 h at ambient température then treated with water. The mixture is extracted with EtOAc, dried over Na₂SO4, filtered, and concentrated in vacuo. The crude is purified by flash chromatography (SiO₂,30 to 70%EtOAc in Hep) to give example 37 (5 mg, 16%).

The following compounds are prepared in similar fashion:

Examples 30,36

Method 20

Synthesls of Example 40

103

To a solution of 1-32 (100 mg, 0.26 mmol) in CH2CI2 (2 mL) is added EDC (60 mg, 0.31 mmol) followed by acrylic acid (22 mg, 0.31 mmol). The mixture is stirred at ambient température for 1 h then directly purified by flash chromatography (SiO₂, CH2CI2 to 5 5%MeOH in CH2CI2) to give example 40 (15 mg, 13%).

The following compounds were made in similar fashion:

Examples 86,89 (R-10 used instead of acrylic acid)

Method 21

Synthesls of Example 60

104

To a solution of 1-60 (43 mg, 0.10 mmol) in DME (2 mL) is added R-12 (65 mg, 0.18 mmol), SiliaCat DPP-Pd (50 mg, 0.01 mmol), and potassium carbonate (500 mg). The mixture is heated at 140° C in a microwave for 2 h then concentrated in vacuo. The crude is purified by flash chromatography (SiO₂,0 to 4%MeOH in CH₂C1₂) to give 1-61 (38 mg, 72%) m/z 519.2 [M+H].

1-61 (38 mg, 0.073 mmol) is dissolved in CH₂C1₂ (2 mL) and treated with 4.0M HCl in 10 dioxane (3 mL). The mixture is stirred for 2 h at ambient température then volatiles are removed in vacuo. The residue is dissolved în CH₂C1₂ (2 mL) and treated with acrylic acid (5 mg, 0.073 mmol) and EDC (14 mg, 0.073 mmol). The mixture is stirred for 1 h at

105 ambient température then partitioned between water and CH2CI2. The mixture is filtered through a phase séparator® and organics are collected and concentrated in vacuo. The crude is purified by flash chromatography (S1O2, CH2CI2 to 8%MeOH in CH2CI2) to give example 60 (13 mg, 57%).

The following compound was made in similar fashion:

Example 61

Method 22

Synthesis of Example 72

A flask is charged with 1-60 (4.0 g, 9.5 mmol), 4-hydroxyphenytboronic acid (1.9 g, 14

106 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.67 g, 0.95 mmol), potassium carbonate (25 g, 18 mmol) and treated with DMF (40 mL) and water (10 mL). The mixture is heated in the microwave at 140° C for 90 min. The mixture is cooled to ambient température then treated with saturated aqueous NHjCl, extracted with EtOAc, dried over Na2SO₄, fîltered, and concentrated in vacuo. The crude is purified by flash chromatography (S1O2, 20 to 50% EtOAc in Hep) to give 1-62 (2.0 g, 54%) m/z [M+H].

To a solution of 1-62 (90 mg, 0.23 mmol) in CH2CI2 (7 mL) is added 3-tolylboronic acid (95 mg, 0.70 mmol), Cu(OAc)2 (300 mg), pyridine (1 mL), TEA (1 mL), and molecular steves (4Â). The mixture is stirred at ambient température open to air for 12 h. The mixture was fîltered through a silica gel pad and volatiles from the filtrate are removed in vacuo. The crude is purified by RHPLC to afford 1-63 (61 mg, 55%) m/z 477.1 [M+H].

To a solution of 1-63 (55 mg, 0.115 mmol) in CH2CI2 (3 mL) is added TFA (1 mL). The mixture is stirred at ambient température for 2 h then treated with saturated aqueous Na₂CO3. The layers are separated and volatiles from the organics are removed in vacuo to afford a residue. The residue is dissolved in DMF (4 mL) and treated with acrylîc acid (0.6 mL) and EDC (38 mg, 0.25 mmol). The mixture is stirred at ambient température 12 h then directly purified by RHPLC to give example 72 (17 mg, 34%).

The following compounds are prepared in similar fashion:

Examples 62-71,73-76

Method 23

Synthesis of Example 90

107

To a solution of 1-31 (0.20 g, 0.55 mmol) in DMA (3 mL) is added DIEA (0.15 mL, 0.86 mmol) and R-13 (0.12 g, 0.71 mmol). The mixture is heated at 50 °C for 18 h then cooled to ambient température. The mixture is partitioned between water and EtOAc. The 5 organics are collected, dried over Na₂SO4, filtered, and concentrated in vacuo. The crude is purified by RHPLC to afford 1-64 (0.15 g, 62%) mtz 447.1 [M+H].

To a solution of 1-64 (70 mg, 0.16 mmol) in DMF (2 mL) is added TBTU (60 mg, 0.19 mmol) and DIEA (0.06 mL, 0.19 mmol). The mixture is stirred for 5 min then treated with 10 a 2.0M solution of methylamine in THF (0.24 mL, 0.47 mmol). The mixture is stirred at ambient température for 16 h then treated with saturated aqueous ammonium chloride.

The mixture is extracted with EtOAc, dried over Na₂SO4, filtered, and concentrated in vacuo. The crude is purified by RHPLC to afford example 90 (7 mg, 10%).

108

Method 24

Synthesis of Example 93

O

1-31 Ex 93

To a solution of 1-31 (100 mg, 0.28 mmol) in CH₂Ci₂ (5 mL) is added TBTU (91 mg, 0.28 mmol) and R-14 (prepared according to J. Med. Chem. 2001,44, 2719-2734, 70 mg, 0.41 mmol). The mixture is stirred at ambient température over night then filtered and purified by flash chromatography (SiO₂, CH₂C1₂ to 10%MeOH with 1% ammonium hydroxide) to give example 93 (58 mg, 41%).

Method 25

Synthesis of Example 58

109

Ex 58

To a solution of 1-47 (29 mg, 0.074 mmol) in CH2CI2 (2 mL) is added EDC (92 mg, 0.38 mmol) and R-10 (20 mg, 0.24 mmol). The mixture is stirred at ambient température for 1 5 h then partitioned between water and CH2CI2. The mixture is filtered through a phase separator® and organics are collected and concentrated in vacuo. The crude is purified by flash chromatography (SiO₂,20 to 100%EtOAc in Hep) to give example 58 (23 mg, 68%).

The following compounds are made in similar fashion:

Examples 78,85,52,53

Method 26

Synthesis of Example 79

110

1-43

To a solution of 1-43 (65 mg, 0.16 mmol) in CH2CI2 (2 mL) is added EDC (37 mg, 0.19 mmol) followed by acrylic acid (14 mg, 0.19 mmol). The mixture is stirred at ambient 5 température for 1 h then directly purified by flash chromatography (S1O2, CH2CI2 to 5%MeOH in CH2CI2) to give example 79 (14 mg, 19%).

The following compounds were made in similar fashion:

Exemples 34,50,51,57,84

Method 27

Synthesis of Example 77

111

EDC. Hunig's base

1-54

A solution of morpholine (35 mg, 0.4 mmol), (E)-4-bromo-but-2-enoic acid (79 mg, 0.48 mmol), and Hunig’s base (0.21 mL, 1.2 mmol) in DMF (2 mL) is stirred for 18 h. To this mixture is added EDC (71 mg, 0.37 mmol). The mixture is stirred for 5 min then treated 5 with 1-54 (120 mg, 0.31 mmol) and stirred for 18 h. Saturated aqueous ammonium chloride is added (4 mL) and mixture is extracted with EtOAc, dried over sodium sulphate, concentrated, and then purified by préparative TLC (SiOi, 30%MeOH in EtOAc) to provide example 77 (64 mg, 38%).

The following compounds are made in similar fashion:

Examples 98-100

Method 28

Synthesls of Example 80

Ex 50

112

To a solution of 1-57 (200 mg, 0.51 mmol) in DMF (2 mL) is treated with DIEA (150 mg, 1.1 mmol), EDC (130 mg, 0.67 mmol), followed by acrylic acid (0.05 mL, 0.67 mmol). The solution is stirred for 16 h then treated with saturated aqueous ammonium chloride. The mixture is extracted with EtOAc, dried over Na₂SO4, filtered, and concentrated in vacuo. The crude is purified by flash chromatography (SiO₂, EtOAc to 10%MeOH in EtOAc) to afford example 80 (52 mg, 23%).

The following compounds are prepared in similar fashion:

Examples 35,44,54,81,82

Method 29

Synthesls of Example 41

To a solution of 1-53 (100 mg, 0.26 mmol) in DMF (2 mL) is added EDC (54 mg, 0.28 mmol) and R-10 (23 mg, 0.28 mmol). The mixture is stirred at ambient température for 16 h then partitioned between saturated aqueous ammonium chloride and EtOAc. The organics are collected, dried over Na₂SO4, filtered, and concentrated. The crude is purified by flash chromatography (SÎO₂, EtOAc to 10%MeOH in EtOAc) to give example 41 (24 mg, 21%).

113

The following compounds are prepared in simîlar fashion:

Examples 83,91,92

Method 30

Synthesis of Example 87

To a solution of the bis HCl sait of 1-51 (55 mg, 0.12 mmol) in CH2CI2 (1.7 mL) is added TEA (29 mg, 0.29 mmol), EDC (34 mg, 0.17 mmol), and R-10 (15 mg, 0.17 mmol). The mixture is stirred at ambient température for 2 h then partitioned between water and 10 CH2CI2 then filtered through a phase separator®. The organics are collected and concentrated in vacuo to afford a residue that is purified by flash chromatography (S1O2, CH2CI2 to 45%MeOH in CH2CI2) to afford example 87 (25 mg, 46%).

The following compounds were prepared in similar fashion:

Examples 59,46 (acrylic acid used instead of R-10)

Method 31

Synthesis of Example 97

114

To a suspension of NaH (60% dispersion in minerai oïl, 160 mg, 4.0 mmol) in DMF (5 mL) is added 1-9 (0.93 g, 3.35 mmol). After 5 min of stirring, a solution of 1-67 (1.28 g, 3.35 mmol) in DMF (5 mL) is added. The mixture is heated at 70 °C overnight then 5 cooled to ambient température and partitioned between EtOAc and water. The organics are collected and washed with water and brine, dried, and concentrated in vacuo. The crude is purified by flash chromatography (S1O2,0-70% EtOAc in Heptane) to afford 1-68

115 (0.59 g, 37%) m/z 486.7 [M+H].

1-68 (059 g, 1.22 mmol) is diluted with EtOH (1 mL) and water (05 mL) and Hydridofdimethylphosphinous acid kP) [hydrogen bis(dimethylphosphinito-kP)J platinum (II) (0.07 g, 0.163 mmol) is added. The mixture is heated at 80 °C ovemight then 5 concentrated in vacuo. The residue is dissolved in CH2CI2 then filtered and concentrated to afford 1-69 (0.28 g, 45%) m/z 504.7 [M+H].

1-69 (50 mg, 0.1 mmol) is dissolved in CH₂O₂ (0.8 mL) and TFA (0.08 mL). The mixture is stirred for 3 h then partitioned between CH₂C1₂ and aqueous saturated NaHCOj. Organics are combined and concentrated to give a residue that is treated with a prestirred 10 (15 min) solution of acrylic acid (10 pL, 0.13 mmol), EDC (35 mg, 0.18 mmol), and

Hunig’s base (70 pL, 0.38 mmol) in DMF (1.0 mL). The mixture is stirred ovemight then diluted with aqueous saturated ammonium chloride and extracted with EtOAc. The organics are combined, washed with brine, dried over Na2SO₄, filtered, and concentrated in vacuo. The crude is purified by flash chromatography (SiO₂) to afford example 97 (5 mg, 15 88%).

Method 32

Synthesis of Example 101

116

To a solution of 3-amino-4-cyanopyrazole (100 g, 0.9 mol) in DMF (1 L) is added NBS (1975 g, 1.1 mol) and mixture is stirred for 10 h at ambient température. The mixture is concentrated in vacuo then dissolved in EtOAc and washed with brine (8 x). The organics 5 are collected and concentrated in vacuo to afford 1-70 (50 g, 29%) m/z 187.0 [M+].

A vial is charged with 1-70 (1.0 g, 5.35 mmol), 2-phenoxy-5-(4,455-tetramethyl[l,3,2]dioxaborolan-2-yl)-pyridine (2.07 g, 6.95 mmol), tetrakis(triphenylphosphine) palladium (0) (0.62 g, 0535 mmol) and dissolved in aqueous potassium carbonate (10 mL, 2.0 M) and DME (6 mL). The mixture is heated at 130 °C for 3 h in a microwave. The 10 mixture is filtered then diluted with water, extracted with EtOAc, dried over sodium sulphate, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (SiO₂, 0-100%EtOAc in heptanes) to give 1-71 (1.18 g, 80%) m/z 278.0 [M+H].

Sodium hydride (60%dispersion in minerai oil, 100 mg, 25 mmol) is added to a solution of 15 1-71 (530 mg, 1.9 mmol) in DMF (75 mL). The mixture is stirred for 5 min then treated with 1-1 (840 mg, 2.3 mmol) and heated at 70 °C for 18 h. The solution is cooled to

117 ambîent température then partitioned between EtOAc and water. Organics are collected, dried, filtered, and concentrated in vacuo to afford a residue that is purified by flash chromatography (SiO₂,0-100%EtOAc in heptanes) to give 1-72 (310 mg, 35%) m!z 473.2 [M+H].

1-72 (0.31 g, 0.66 mmol) is diluted with EtOH (5 mL) and water (05 mL) and Hydrido(dimethylphosphinous acid kP) [hydrogen bis(dimethylphosphinito-kP)] platinum (II) (28 mg, 0.066 mmol) is added. The mixture is heated at 80 °C ovemight then concentrated in vacuo. The residue is dissolved in CH2CI2 then filtered and concentrated to afford a residue that is dissolved in TFA (5 mL) and stirred for 3 h at ambient température then concentrated in vacuo. The residue is dissolved in MeOH and passed through an Agitent Stratosphères PL-HCO3 MP SPE cartridge and concentrated in vacuo to afford I73 (0.25 g, 98%) m!z 391.2 [M+H].

1-73 (110 mg, 0.28 mmol) is treated with a prestirred (15 min) solution of acrylic acid (21 pL, 0.13 mmol) and EDC (65 mg, 0.34 mmol) in DMF (2.0 mL). The mixture is stirred ovemight then diluted with aqueous saturated ammonium chloride and extracted with EtOAc. The organics are combîned, washed with brine, dried over Na₂SO4, filtered, and concentrated in vacuo. The crude is purified by flash chromatography (SiO₂, 10%MeOH in EtOAc) to afford example 101 (32 mg, 26%).

The following compounds are made in similar fashion:

Examples 102-103,110

Method 33

Synthesls of Example 122

118

1-74

Ex 122

To a solution of 1-71 (1.1g, 3.97 mmol) in DMF (20 mL) is added NaH (60%dispersion in minerai oil, 190 mg, 4.76 mmol). The mixture is stirred for 5 min then treated with 1-4 (1.82 g, 4.76 mmol) and heated at 70 °C for 18 h. The mixture is cooled then partitioned 5 between EtOAc and water. Organics are collected, dried over NaiSOj, filtered, and concentrated in vacuo to give a residue that is purified by flash chromatography (SiO;, 080%EtOAc in heptanes) to give 1-74 (520 mg, 27%) m/z 487.3 [M+H] and I-7S (500 mg, 26%) m/z 487.3 [M+H].

1-74 (250 mg, 0.514 mmol) is diluted with EtOH (5 mL) and water (0.5 mL) and 10 Hydrido(dimethylphosphinous acid kP) [hydrogen bis(dimethylphosphinito-kP)] platinum (II) (22 mg, 0.051 mmol) is added. The mixture is heated at 80 °C ovemight then concentrated in vacuo. The residue is dissolved in CH2CI2 then filtered and concentrated to afford a residue that is dissolved in TFA (5 mL) and stirred for 3 h at ambient température

119 then concentrâted in vacuo. The residue is dissolved in MeOH and passed through an Agitent Stratosphères PL-HC03 MP SPE cartridge and concentrated in vacuo to afford I76 (0.206 g, 98%) m!z 405.3 [M+H].

1-76 (254 mg, 0.63 mmol) is treated with a prestirred (15 min) solution of R-10 (69 mg, 5 0.82 mmol) and EDC (144 mg, 0.75 mmol) in DMF (2.0 mL). The mixture is stirred ovemight then diluted with aqueous saturated ammonium chloride and extracted with EtOAc. The organics are combîned, washed with brine, dried over Na₂SÛ4, fîltered, and concentrated in vacuo. The crude is purified by flash chromatography (SiO₂, 10%MeOH in EtOAc) to afford example 122 (48 mg, 16%).

The fotlowing compounds are made in similar fashion:

Examptes 114,117-120,123,150-152

Method 34

Synthesis of Example 104

120

A vial is charged with 1-70 (050 g, 2.67 mmol), 4-isopropoxyboronic acid (058 g, 3.21 mmol), tetrakis(triphenylphosphine) palladium (0) (0.43 g, 0.37 mmol) and dissolved in aqueous potassium carbonate (4 mL, 2.0 M) and DME (3 mL). The mixture is heated at 5 130 °C for 3 h in a microwave. The mixture is fîltered then diluted with water, extracted with EtOAc, dried over sodium sulphate, fîltered, and concentrated in vacuo. The residue is purified by flash chromatography (S1O2, 0-80%EtOAc in heptanes) to give 1-77 (0.473 g, 73%) mlz 2435 [M+H].

Sodium hydride (60%dispersion in minerai oil, 55 mg, 1.37 mmol) is added to a solution of 10 1-77 (300 mg, 1.24 mmol) in DMF (5 mL). The mixture is stirred for 5 min then treated with 1-1 (550 mg, 1.47 mmol) and heated at 70 °C for 18 h. The solution is cooled to ambient température then partitioned between EtOAc and water. Organîcs are collected, dried, fîltered, and concentrated in vacuo to afford a residue that is purified by flash chromatography (SiO₂, 0-100%EtOAc in heptanes) to give 1-78 (200 mg, 37%) m/z 438.6

12t [M+H].

1-78 (190 mg, 0.43 mmol) is diluted with EtOH (4 mL) and water (2 mL) and Hydrido(dimethylphosphinous acid kP) [hydrogen bis(dimethylphosphinito-kP)] platinum (II) (11 mg, 0.026 mmol) is added. The mixture is heated at 80 °C ovemight then 5 concentrated in vacuo. The residue is dissolved in CH2CI2 then filtered and concentrated to afford a residue that is dissolved in CH2CI2 (5 mL) and TFA (1 mL) and stirred ovemight at ambient température then concentrated in vacuo. The residue is dissolved in MeOH and passed through an Agitent Stratosphères PL-HCO3 MP SPE cartridge and concentrated in vacuo to afford 1-79 (110 mg, 71%).

1-79 (40 mg, 0.11 mmol) and acrylic acid (10 mg, 0.14 mmol) in DMF (5 mL) is treated with HATU (88 mg, 0.17 mmol) and Hunig’s base (60 pL, 0.34 mmol) in DMF (2.0 mL). The mixture is stirred ovemight then concentrated in vacuo. The crade is purified by RHPLC to afford example 105 (25 mg, 54%).

The following compounds are made in similar fashion:

Examples 104, 106-109, 111-113, 115-116, 124, 133, 134-136, 138-139, 141-144, 147149,166

Method 35

122

1) Pt (II). Η,ΟΈΐΟΗ

2) TFA

A vial is charged with 1-70 (0.45 g, 2.41 mmol), 4-n-propoxyboronic acid (0.48 g, 2.65 mmol), tetrakis(triphenylphosphine) palladium (0) (0.28 g, 0.24 mmol) and dissolved in aqueous potassium carbonate (4.8 mL, 2.0 M) and dioxane (2 mL). The mixture is heated 5 at 130 °C ovemight. The mixture is fîltered then diluted with water, extracted with EtOAc, dried over sodium suiphate, fîltered, and concentrated in vacuo, The residue is purified by flash chromatography (SiO₂, 0-6%MeOH in CH₂C1₂) to give 1-80 (0.400 g, 69%) m!z 242.4 [M+J.

Sodium hydride (60%dispersion in minerai oil, 33 mg, 0.82 mmol) is added to a solution of 10 1-80 (200 mg, 0.74 mmol) in DMF (5 mL). The mixture is stirred for 5 min then treated with 1-6 (318 mg, 0.82 mmol) and heated at 70 °C for 18 h. The mixture is concentrated in vacuo and purified by flash chromatography (SiO₂, 35%EtOAc in heptanes) to give 1-81 (130 mg, 39%) m!z 452.9 [M+H].

1-81 (130 mg, 0.29 mmol) is diluted with EtOH (15 mL) and water (05 mL) and

123

Hydrido(dimethylphosphinous acid kP) [hydrogen bis(dimethylphosphinito-kP)] platinum 01) (13 mg, 0.029 mmol) is added. The mixture is heated at 80 °C ovemight then concentrated in vacuo. The residue is dissolved in EtOAc then filtered and concentrated to afford a residue that is dissolved in CH2CI2 (1 mL) and TFA (1 mL) and stirred for 1 h at 5 ambient température then concentrated in vacuo. The residue is dissolved in MeOH and passed through an Agilent Stratosphères PL-HCO3 MP SPE cartridge and concentrated in vacuo to afford 1*82 (80 mg, 84%).

1-82 (130 mg, 0.35 mmol) is treated with a prestirred (15 min) solution of acrylic acid (30 mg, 0.42 mmol) and EDC (81 mg, 0.42 mmol) in DMF (2.0 mL). The mixture is stirred 10 ovemight then diluted with aqueous saturated ammonium chloride and extracted with

EtOAc. The organics are combined, dried over Na₂SO4, filtered, and concentrated in vacuo. The crude is purifîed by RHPLC to afford example 125 (30 mg, 20%).

The following compounds are made in similar fashion:

Examples 130,132,145-146,153,155-156,159,162-163,165

Method 36

Synthesls of Example 126

124

1) Pi (11), H,O/EtOH

1-84 ------------------------

2) TFA

Ex 128

Sodium hydride (60%dispersion in minerai oil, 80 mg, 2.02 mmol) is added to a solution of 1-80 (445 mg, 1.84 mmol) in DMF (5 mL). The mixture is stirred for 5 min then treated with 1-4 (770 mg, 2.02 mmol) and heated at 70 °C for 18 h. The mixture is diluted with 5 saturated aqueous ammonium chloride, extracted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (SiO₂, 06%MeOH in CH2CI2) to give 1-81 (200 mg, 24%) and 1-84 (300 mg, 36%) m/z 4525 [M+H].

1-84 (300 mg, 0.66 mmol) is diluted with EtOH (15 mL) and water (0.5 mL) and 10 Hydrido(dimethy!phosphinous acid kP) [hydrogen bis(dimethylphosphinito-kP)] platinum (II) (28 mg, 0.066 mmol) is added. The mixture is heated at 80 °C for 72 h then concentrated in vacuo. The residue is dissolved in EtOAc then filtered and concentrated to afford a residue that is dissolved in CH2CI2 (1 mL) and TFA (1 mL) and stirred for 1 h at

125 ambient température then concentrated in vacuo. The residue is dissolved in MeOH and passed through an Agilent Stratosphères PL-HCO3 MP SPE cartridge and concentrated in vacuo to afford 1-85 (270 mg).

1*85 (80 mg, 0.22 mmol) is treated with a prestirred (15 min) solution of acrylic acid (19 5 mg, 0.26 mmol) and EDC (50 mg, 0.26 mmol) in DMF (2.0 mL). The mixture is stirred ovemight then diluted with aqueous saturated ammonium chloride and extracted with EtOAc. The organics are combined, dried over Na^SO^ fïltered, and concentrated in vacuo. The crude is purified by RHPLC to afford example 126 (7 mg, 8%).

The following compounds are made in similar fashion:

Examples 131

Method 37

Synthesls of Example 140

Ex 140

1-82 (80 mg, 0.22 mmol) is treated with a prestirred (15 min) solution of R-10 (24 mg, 15 0.28 mmol) and EDC (50 mg, 0.26 mmol) in DMF (2.0 mL). The mixture is stirred ovemight then diluted with aqueous saturated ammonium chloride and extracted with EtOAc. The organics are combined, dried over NajSO^ fïltered, and concentrated in vacuo. The crude is purified by RHPLC to afford example 140 (14 mg, 15%).

126

The following compounds are made in similar fashion:

Example 128,137,154,157-158,160-161,164,167-168

Method 38

Synthesis of Example 127

1-85 (70 mg, 0.19 mmol) is treated with a prestirred (15 min) solution of R-10 (21 mg, 0.25 mmol) and EDC (44 mg, 0.23 mmol) in DMF (2.0 mL). The mixture is stirred ovemight then diluted with aqueous saturated ammonium chloride and extracted with EtOAc. The organics are combined, dried over Na₂SO4, filtered, and concentrated in vacuo. The crude is purified by RHPLC to afford example 127 (13 mg, 16%).

The following compounds are made in similar fashion:

Example 129

Description of Biological Properties

BTK Assav

An HTRF assay (Cisbio KinEASE-TK cal # 62TK0PEC) was performed to quantitate the ability of test compounds to inhibit BTK mediated phosphorylation of substrate. Assays were assembied in 384 weil plates where 6nM of full-length human His-tagged BTK (Life

127

Technologies cat # PV3587) and test compound at varying concentrations were preincubated for 15 minutes at 28°C. Then, luM of TK substrate-biotin and 30uM ATP were added and incubated for an additional 30 minutes at 28°C. Phospohrylation was detected by adding 623nM Streptavidin-XL665 and TK-Antibody Cryptate diluted 1:100 in HTRF détection buffer (Cisbio cat # 62SDBRDF) and incubated for 60 minutes at RT. The plate was read on an Envision plate reader and the fluorescence is measured at 620nm (cryptate) and 665nm (XL665). A ratio is calculated (665/620) and converted to POC relative to control and blank wells.

Assay buffer:

50mM HEPES (Invitrogen #15630),0.01% Brij-35 (sigma #B4184), lOmM MgC12 (Sigma M1028), ImM EGTA (Ambion AM9262) and lOOuM sodium orthovanedate ( Sigma S6508), ImM DTT (Sigma D5545) and lOnM supplément enzyme buffer (Cisbio cat# 61SEBALB).

Preferred compounds for the treatment of autoimmune disorders exhibit sélective inhibition of BTK over other kinases such as EGFR. The compounds described herein show a range of selectivities against EGFR as measured in cellular assays (BTK activity measured by CD69 expression in primary CD19⁺ cells; EGFR activity measured by EGFR phosphorylation in A431 cells). See Table II.

Table II

Example	B-cell CD69ICso(nM)	A431 p-EGFRICjo (nM)
54	1.2	6.6
46	2.0	120
161	2.1	400
164	13	420
41	1	430
81	0.9	790
160	43	1200
78	23	1800

128

165	10	3700
107	8.2	4200
28	9	4700
163	15	5200
112	41	5800
113	24	6300
115	7.8	6400
40	20	>10000
106	30	>10000
158	58	>10000

Inhibition of B-cell activation measured bv CD69 expression

Primary CD19⁺ cells were purified from healthy frozen peripheral blood mononuclear cells (AllCells, Emeryville, CA) and negatively selected by magnetic séparation, >97% purity ( 5 Stemcell Technologies, Vancouver, CA). Cells were collected and plated in a 96 fiat bottom plate at a concentration of 2xlO^s/well in RPMI media containing 10% FBS, rested for 1 hour at 37°c. Cells were treated with inhibitor in duplicates or vehide control in 1% DMSO final concentration for 1 hour at 37°c, 5% CO₂. Cells were then stimulated with 12.5ug/ml Goat F(ab’)₂ anti-human IgD (SouthemBiotech, Birmingham, AL) for 18-24 10 hours at 37 °C, 5% CO₂. Cells were collected and stained for APC-CD19, clone HIB19 and PE-CD69, clone FN50 (antibodies purchased from BD Bioscience, San José, CA). B cells were analyzed by flow cytometry using a BD LSRII or BD FACsCanto Flow Cytometer. Viable cells were gated, and CD69 percentage was determined using FlowJo software.

Inhibition of EGFR autophosphorvlation in A431 human épithélial cells stimulated with épithélial growth factor

A431cells (ATCC # CRH555 FZ) are thawed and plated in DMEM containing 10% FBS in a 384-well tissue culture treated plate at 15,000 cells/well. After incubating for 24 hours

129 at 37 °C, 5 % CO2, the cells are treated with test compound (1% DMSO final concentration) and incubated for 16 hours at 37 °C, 5 % C0₂. EGF (Millipore, 01-107) is added at a final concentration of 60 ng/mL and incubated for 10 minutes. The medium is removed, the cells are lysed, and phospho EGFR is measured (Meso Scale Diagnostics, N31CB-1).

Therapeutic Use

On the basis of their biological properties the compounds of formula (I) according to the invention, or their tautomers, race mates, enantiomers, diastereomers, mixtures thereof and the salts of ail the above-mentioned forms are suitable for treating autoimmune and allergie disorders in that they exhibit good inhibitory effect upon BTK.

Such diseases include for example: rheumatoid arthritis, systemic lupus erythromatosis, scie rode rma, asthma, allergie rhinitis, allergie eczema, B cell lymphoma, multiple sclerosis, juvénile rheumatoid arthritis, juvénile idiopathic arthritis, inflammatory bowel disease, graft versus host disease, psoriatic arthritis, ankylosing spondylitis and uveitis.

The compounds of formula (I) may be used on their own or in combination with other active substances according to the invention, optionally also in combination with other pharmacologically active substances.

Suitable préparations include for example tablets, capsules, suppositories, solutions particularly solutions for injection (s.c., i.v., i.m.) and infusion - élixirs, émulsions or dispersible powders. The content of the pharmaceutically active compound(s) should be in the range from 0.1 to 90 wt.-%, preferably 05 to 50 wt.-% of the composition as a whole, Le. in amounts which are sufficient to achieve the dosage range specified below. The doses specified may, if necessary, be given several times a day.

130

Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gélatine, fabricants such as magnésium stéarate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilîties the core may also consist of a number of layers. Similarly the tablet coating may consist of a number of layers to achieve delayed release, possîbly using the excipients mentioned above for the tablets.

Syrups or élixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.

Solutions for injection and infusion are prepared in the usual way, e.g. with the addition of isotonie agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkalî métal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving aids, and transferred into injection vials or ampoules or infusion bottles.

131

Capsules containing one or more active substances or combinations of active substances may for exampte be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gélatine capsules.

Suitable suppositories may be made for example by mixing with carriers provided for this purpose such as neutral fats or polyethyleneglycol or the dérivatives thereof.

Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut 10 or sesame oil), mono- or polyfunctional alcohols (e.g. éthanol or glycerol), carriers such as e.g. naturel minerai powders (e.g. kaolins, clays, talc, chatk), synthetic minerai powders (e.g. hîghly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and potyvinylpyrrolidone) and lubricants (e.g. magnésium stéarate, talc, stearic acid and t5 sodium lauryl sulphate).

The préparations are administered by the usuat methods, preferably by oral or transdermal route, most preferably by oral route. For oral administration the tablets may of course contain, apart from the above-mentioned carriers, additives such as sodium citrate, calcium 20 carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gélatine and the like. Moreover, lubricants such as magnésium stéarate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.

For parentéral use, solutions of the active substances with suitable liquid carriers may be used.

132

The dosage for intravenous use is from 1 - 1000 mg per hour, preferably between 5 and 500 mg per hour.

However, it may sometimes be necessary to départ from the amounts specified, depending 5 on the body weight, the route of administration, the individual response to the drug, the nature of its formulation and the time or interval over which the drug is administered. Thus, in some cases it may be sufficient to use less than the minimum dose given above, whereas in other cases the upper limit may hâve to be exceeded. When administering large amounts it may be advisable to divide them up into a number of smaller doses spread over 10 the day.

Ail patent and non-patent documents or literature cited in this application are herein incorporated by reference in their entirety.

Claims

Claims

1. A compound of the formula (I)

A ring is:

RiisNfRa^or hydrogen;

Cy is aryl or heteroaryl each is substituted by R₂ and optionally substituted by halogen, halo Cm alkyl, Cm alkyl and Cm alkoxy;

R₂ is chosen from:

L-Ar, Cm alkyl and Cm alkoxy, each Ar, Cm alkyl and Cm alkoxy are optionally substituted by halogen, halo Cm alkyl, Cm alkyl, R3-S(O)_ro-, -CN, -C(O)-N(R3)₂ or Cm alkoxy;

Usa linker chosen from a bond, O, >C(O), -(CH₂)_n-, -O-(CH₂)_n-, -N(R3)-, -N(R3)-(CH₂)_n, -(CH₂)_n-N(R3)-, -C(O)-N(R₃)-, -C(O>N(R₃>(CH₂)_n-,-N(R3)-C(O)-N(R₃)-, -N(R₃)-C(O)-, -S(O)_m-N(R3)- and -N(R3)-S(O)_m-, wherein the -CH₂- in each Lcan hâve 1-2 hydrogens replaced by Cm alkyl, said Cm alkyl groups can optionally cyclize to form a C3-Û

134 cycloalky! ring;

Ar is carbocycle, heterocycy! or heteroaryl;

Xi is a linker chosen from a bond, -(CH₂)_n-;

Y is chosen from C7-C10 spirocycle optionally containing 0-1 ring nitrogen atoms, a nitrogen containing mono- or bi-cyclic heterocycle, carbocycle, aryl, each substituted by one R4;

R41S ⁵ wherein Rj cannot be hydrogen,

135 each n is independently 1-4;

each m is independently 0-2;

each R₃ is independently chosen from hydrogen or Cm alkyl;

each Rj is independently chosen from hydrogen, Cm alkyl, Cm atkoxy, Cm alkylCM alkoxy, -(CHîJn-heterocycle and heterocycle each heterocycle optionally substituted by halogen, OH or R₃-S(O)_ra-;

each group defined above for Cy, R1-R5, Xj and Y can be where possible partially or futty halogenated;

or a pharmaceutically acceptable sait thereof.
2. The compound according to daim 1 and wherein

A ring is:

or a pharmaceutically acceptable sait thereof.
3. The compound according to daim 2 and wherein

Cy is phenyl, pyridinyl, pyridazinyl, pyrimidinyt or pyrazinyl each is substituted by R2 and optionally substituted by F, Cl or Cm alkoxy;

R2 is chosen from:

L-Ar and Cm alkoxy, each Ar and Cm atkoxy are optionally substituted by F, Cl, Cm alkyl, R₃-S(O)₂-, -CN, -C(O)-NH(R₃) or Cm alkoxy;

L is a tinker chosen from a bond, O, >C(O), -CH2-, -O-CH2-, -NH-, -NH-CH2-, -CH2-NH-,

136

-C(O)-NH-CH₂-,-NH-C(O)-NH- and -N(R₃)-S(O)_m-;

Ar is phenyl, pyridinyl, pyridazinyl, pyrimidînyl, pyrazinyl, benzoxazolyl, indolyl, isoindolyl, benzofuranyl, benzimidazolyl, benzothiazolyl, piperidinyl, piperazinyl or pyrrolidinyl or a pharmaceutically acceptable sait thereof.
4. The compound according to claim 3 and wherein

Cy is phenyl or pyridinyl, each is substituted by R2 and optionally substituted by F, Cl or Ci-2 alkoxy;

R2 is chosen from:

L-Ar and C1.3 alkoxy, each Ar and C1.3 alkoxy are optionally substituted by F, Cl, Cm alkyl, CH₃-S(O)2-, -CN, -C(O)-NH(R₃) or Ci.₂ alkoxy;

L is a linker chosen from a bond, O, >C(O), -CH2-, -O-CH2-, -NH-, -NH-CH2-, -CH2-NH-, -C(O)-NH-CH₂-,-NH-C(O)-NH- and -N(R3)-S(O)_ra-;

Ar is phenyl, pyridinyl, pyridazinyl, pyrimidiny], pyrazinyl, benzoxazolyl, indolyl, isoindolyl, benzofuranyl, benzimidazolyl, benzothiazolyl or piperidinyl or a pharmaceutically acceptable sait thereof.
5. The compound according to claim 4 and wherein

Cy is phenyl or pyridinyl, each is substituted by R2 and optionally substituted by F, Cl or Ci .2 alkoxy;

R2 is chosen from:

L-Ar and C1.3 alkoxy, each Ar and C1.3 alkoxy are optionally substituted by F, Cl, Cm alkyl, CH₃-S(O)2-, -CN, -C(O)-NH(CH₃) or Ci.₂ alkoxy;

L is a linker chosen from a bond, O, >C(O), -CH2-, -O-CH2-, -NH-, -NH-CH2-, -CH^-NH-, -C(O)-NH-CH2-,-NH-C(O)-NH- and -N(H)-S(O)₂-;

Ar is phenyl, pyridinyl, benzoxazolyl or piperidinyl or a pharmaceutically acceptable sait thereof.
6. The compound according to claim 5 and wherein

Xi is a linker chosen from a bond and -(CH2)_n-;

Y is chosen from:

137 a heterocycle chosen from piperidinyl and pyrrolidinyl; and phenyl each heterocycle or phenyl substituted by one R,;

R4 is wherein Rjcannot be hydrogen, each R4 is optionally halogenated;

each R5 is independently chosen from hydrogen, C1.3 alkyl, halo C4.3 alkyl, C1.3 alkylCi.3 alkoxy, -CHî-heterocycle and heterocycle each heterocycle optionally substituted by F, Cl, OH and CHj-SfO)?- and each heterocycle chosen from pyrrolidinyl, piperidinyl, morpholinyl and 1,4-oxazepane, or a pharmaceutically acceptable sait thereof.
7. The compound according to daim 6 and wherein Xt is a linker chosen from a bond and -(CH2)_n-;

Y is chosen from:

a spirocycle chosen from

138 a heterocycle chosen from pîperidinyl and pyrrolidinyl; and phenyl each heterocycle or phenyl substituted by one R4; R4IS halogen or hydrogen, or each Rj is independently chosen from hydrogen, C1.3 alkyl, -CF3, C1.3 alkylCi.3 alkoxy, CHi-heterocycle and heterocycle each heterocycle optionally substituted by F, Cl, OH and 10 CHî-S(O)2- and each heterocycle chosen from pyrrolidinyl, pîperidinyl and 1,4-oxazepane, or a pharmaceutically acceptable sait thereof.
8. The compound according to claim 1 and wherein

15 Cy is * J

139 »

» » Cl »

» · ο

> »

140 or a pharmaceutically acceptable sait thereof.

5
9. The compound according to claim 8 and wherein

X-Y = » I ♦

141

142

5 a pharmaceutically acceptable sait thereof.
10. The compound according to claim 9 and wherein

A ring is:

143 thereof.

or a pharmaceutically acceptable sait
11. The compound according to claim 9 and wherein

A ring is:

or a pharmaceutically acceptable sait thereof.
12. The compound according to claim 9 and wherein

A ring is:

or a pharmaceutically acceptable sait thereof.
13. The compound according to claim 9 and wherein

A ring is:

or a pharmaceutically acceptable sait thereof.

144
14. The compound according to claim 2 and wherein

R₂is

L-Ar;

L is a linker chosen from a bond, O, and -O-(CH2)_n-; n is 1-3;

Ar is carbocycle or heterocycle.
15. The compound according to claim 14 and wherein Ar is C3.5 cycloalkyl or tetrahydrofuranyl;

n = l.
16. The compound according to claim 15 and wherein

L-Ar is or
17. The compound according to claim 2 and wherein

R2 is:

, -OCH₂CH₃, -OCH₂CH2CHj, -OCH₃ -OCF₃ or -OCH₂CF₃.
18. A compound chosen from:

145

146

147

148

149

150

151

152

153

154

155

156

157

158 or the pharmaceutically acceptable salts thereof.

5
19. A compound chosen from:

159

160

161

162

163

164

165

166

a Y ç< A V WP Y* 7 Il γΎο >f“ O ^x ζΧ γΑ° °0γγ> ^χ' ο Ç OyoY 5-/\ ο ¹

r17161

168 or the pharmaceutically acceptable salts thereof.
20. A pharmaceutical composition comprising a therapeutically effective amount of a

5 compound according to claim 1 or a pharmaceutically acceptable sait thereof.
21. Use of a compound according to claim 1 or a pharmaceutically acceptable sait thereof in the manufacture of a médicament for treating a disease chosen from rheumatoîd arthritis, systemic lupus erythromatosis, scleroderma, asthma, allergie rhïnitis, allergie eczema, B

10 ce!! lymphoma, multiple sclerosis, juvénile rheumatoîd arthritis, juvénile idiopathic arthritis, inflammatory bowel disease, graft versus host disease, psoriatic arthritis, ankylosing spondylitis and uveitis